Non-quinolone Inhibitors of Bacterial Type IIA ... - ACS Publications

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Non-quinolone Inhibitors of Bacterial Type IIA Topoisomerases: A Feat of Bioisosterism Claudine Mayer†,‡,§ and Yves L. Janin*,∥,⊥ †

Unité de Microbiologie Structurale, Département de Biologie Structurale et Chimie, Institut Pasteur, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France ‡ Unité Mixte de Recherche 3528, Centre National de la Recherche Scientifique, 25 rue du Dr. Roux, 75724 Paris Cedex 15, France § Cellule Pasteur, Université Paris Diderot, Sorbonne Paris Cité, 75015 Paris, France ∥ Unité de Chimie et Biocatalyse, Département de Biologie Structurale et Chimie, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France ⊥ Unité Mixte de Recherche 3523, Centre National de la Recherche Scientifique, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France S Supporting Information *

Author Information Corresponding Author Notes Biographies Acknowledgments References

1. INTRODUCTION DNA gyrase and topoisomerase IV are the bacterial type IIA topoisomerases. These are ubiquitous nucleic acid-dependent nanomachines, essential to cell life, that solve DNA topological problems resulting from the replication, transcription, and recombination of DNA.1 These enzymes can sever two strands of a duplex DNA, catalyze the passage of another DNA duplex through this break, and then repair it.2,3 When both enzymes are present in a bacterium, topoisomerase IV appears to be useful for chromosome segregation, whereas DNA gyrase is crucial for the initiation and elongation step of DNA synthesis.3 In this case, both are essential for bacterial survival. Deletion of the C-terminal DNA-binding domain of DNA gyrase leads to a loss of its DNA supercoiling ability but the ATP-dependent DNA relaxing capacity, similar to that of topoisomerase IV, remains.4 The similarity of this action on DNA is paralleled by the dual inhibition of these enzymes by the fluoroquinolone antibiotics as well as many other classes of inhibitors described in the following. Moreover, it is only recently that a strong inhibition of both DNA gyrase and topoisomerase IV was recognized to be the key to secure a very low mutation frequency in bacterial strains treated by this class of inhibitors.5,6 The research team who discovered the bacterial DNA gyrase7 also reported quasi-simultaneously that the antibiotic novobiocin (1) inhibits this enzyme,8 thus explaining the reported mutations observed in resistant strains.9 Subsequently, nalidixic acid (2), one of the very first quinolone antibiotics,10 was reported to also target bacterial DNA gyrase,11,12 thus explaining its effect on DNA synthesis13

CONTENTS 1. Introduction 2. Current Views on the Structure of Bacterial Type IIA Topoisomerases 2.1. Overall Structure Stemming from X-Ray Studies 2.2. Effects of Peptides, Peptidic Analogues, and Metal Salts on Type IIA Topoisomerase Activity 2.3. ATPase Domain Structure 3. Assays for Bacterial Type IIA Topoisomerase Inhibition 4. Non-quinolone Inhibitors of Type IIA Topoisomerases 4.1. Aminocoumarin-Containing Compounds: The First Class of DNA Gyrase ATPase Inhibitors 4.2. Cyclothialidines: The Second Class of DNA Gyrase ATPase Inhibitors 4.3. More DNA Gyrase ATPase Inhibitors: A Feat of Bioisosterism 4.4. Several Inhibitors Lacking a Defined Binding Mode to Type IIA Topoisomerases 4.5. Inhibitors Binding the Catalytic Core of Type IIA Topoisomerases 5. Conclusion Associated Content Supporting Information

© 2013 American Chemical Society

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Received: July 22, 2013 Published: December 6, 2013 2313

dx.doi.org/10.1021/cr4003984 | Chem. Rev. 2014, 114, 2313−2342

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(Figure 1). Topoisomerase IV was discovered later14,15 and turned out to be also inhibited by the quinolone class of

Streptococcus pneumoniae, and vancomycin-resistant enterococci.20,21 However, we have excluded from this review the fluoroquinolone (3) and 2-pyridone (4)22 inhibitors, along with related compounds 23−26 including very recent examples27,28as they have already been extensively surveyed.29−38 Major recent achievements regarding this class of inhibitors are the X-ray structural elucidations of their binding mode to type IIA topoisomerases.39−42 Additional reviews, often encompassing the quinolones and other types of type IIA topoisomerase inhibitors, have also been published across the years, thus illustrating the fast evolution in this field.43−55 Downstream from DNA gyrase inhibition, it was demonstrated in Escherichia coli that, at least for inhibitors that induce DNA cleavage (i.e. fluoroquinolones), bacterial death takes place via a massive generation of hydroxyl radicals.56,57 A recent attempt to distinguish off-target effects of antibiotics on bacteria also pointed out that aside from an effect on DNA synthesis, in contrast to the fluoroquinolone ciprofloxacin, a clear dosedependent disruption of RNA synthesis is caused by novobiocin (1).58 The former use of novobiocin (1) in human medicine or the proven benefit of quinolones as antibiotics, along with the increasing pressure caused by the occurrence of bacterial resistance, led in the last 15 years to renewed efforts to design original inhibitors of bacterial type IIA topoisomerases. In the following, we illustrate the different strategies that led to numerous novel chemical series. The design of high-throughput assays and the extensive and often essential recourse of X-ray based structures, along with medicinal chemistry programs,

Figure 1. Structures of novobiocin (1), nalidixic acid (2), and the quinolone class of antibiotics.

antibiotics.16−18 Fluoroquinolones are one of the four chemical scaffolds recurrent in 73% of the antibacterials designed between 1981 and 200519 in attempts to fight the rise of resistant strains of bacteria plaguing hospitals, such as methicillin-resistant Staphylococcus aureus, penicillin-resistant

Figure 2. Structural overview of bacterial type IIA topoisomerase architecture and catalytic cycle. (A) Schematic representation of domain organization of bacterial type IIA topoisomerases (DNA gyrase and topoisomerase IV). They are formed by the association of two subunits: GyrA and GyrB for DNA gyrase, ParC and ParE for Topo IV. (B) Model of global architecture of type IIA topoisomerases based on structures of the isolated domains. They form GyrA2GyrB2 or ParC2ParE2 heterotetramers. Color code is the same as in panel A. (C) Model of the catalytic core, composed of the breakage−reunion and TOPRIM domains, in complex with fluoroquinolone (in green) and a 35-bp DNA (in orange).75 (D) Structure of ATPase domain in complex with ATP.76 (E) Schematic representation of the three main steps of the catalytic cycle. In the first step, the breakage−reunion domain binds a DNA segment termed the gate or G-segment (represented in gray) at the DNA gate. In the second step, the Nterminal ATPase domains dimerize upon ATP binding and capture the DNA duplex to be transported (T-segment, in light gray). In the third step, the T-segment is then passed through a transient break in the G-segment opened by the breakage−reunion domains, the DNA is resealed, and the Tsegment is released through a protein gate, the C-gate, prior to resetting of the enzyme into the open clamp form. 2314


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The first, well-represented by the quinolones, interferes with the catalytic core complex and their action is characterized in biochemical assays by the release of cleaved DNA strands.39−42 The second class, led by novobiocin (1) and many more series described in the following, exerts their effect by blocking the ATPase activity of the enzymes.

were the keys to find many of these. Accordingly, we have illustrated this with figures depicting the X-ray derived binding modes of these inhibitors to bacterial type IIA topoisomerases. The programs PyMol (Molecular Graphics System, version 1.5.0.4, Schrödinger, LLC) and, to a lesser extent, Chimera 1.759 were essential to do this. It is also important to emphasize that most of these discoveries would not have been possible without the fundamental work on overall structures of type IIA topoisomerases described here.

2.2. Effects of Peptides, Peptidic Analogues, and Metal Salts on Type IIA Topoisomerase Activity

Since a fully functional bacterial type IIA topoisomerase requires the assembly of a heterotetramer, it is reasonable to conceive the existence of peptides that would interfere with these protein−protein interactions and thus act as regulators of enzyme function. Interestingly, bacterial plasmids coding for postsegregational killing systems and involving two proteins forming a toxin−antitoxin system were found to act by inhibiting DNA gyrase. The best known is currently the CcdBF/CcdA system of E. coli,77−80 which upon the loss of the plasmid will lead to the release of CcdBF in the daughter cell and its subsequent death.81 To achieve this, the 17.6 kDa protein CcdB was demonstrated, initially by generation and study of resistant strains, to bind to the GyrA subunit and thus inhibit its activity.82−88 More recent experiments with E. coli topoisomerase IV pointed out a lack of effect of CcdBF on this enzyme.89 From these results, crystal structures of CcdBF alone90 and in complex with part of the breakage−reunion domain, which includes the C-gate (PDB code 1X75),91 were obtained. As depicted in Figure 3, this peptide is able to freeze

2. CURRENT VIEWS ON THE STRUCTURE OF BACTERIAL TYPE IIA TOPOISOMERASES 2.1. Overall Structure Stemming from X-Ray Studies

On the basis of evolutionary considerations, the type II topoisomerases have been subclassified into type IIA and IIB families.3 Type IIA includes bacterial DNA gyrase and topoisomerase IV, eukaryal and viral topoisomerases (topoisomerase II), whereas type IIB includes archeal topoisomerase VI and its homologues in plants, a few protists, and a few bacteria.3,60 As depicted in Figure 2, the active DNA gyrase has a heterotetrameric structure composed of two pairs of GyrA and GyrB subunits. A very similar organization is observed for topoisomerase IV, which is composed of dimers of the ParC and ParE subunits. Each of these subunits is made of two structural domains, the N-terminal breakage−reunion domain (depicted in blue) and the carboxy-terminal domain (CTD, depicted in green) for the GyrA or ParC subunits and the ATPase domain (depicted in yellow) along with the TOPRIM domain (depicted in red) for the GyrB or ParE subunits. The double-stranded DNA cleavage−religation site is located in the catalytic core complex composed of the breakage−reunion domain and the TOPRIM domains. The ATPase domain provides, by hydrolysis of ATP, the energy necessary for the extensive conformational changes required. The CTD plays a crucial role in DNA wrapping and is also at the source of the functional differences between DNA gyrases and topoisomerase IV. Crystallographic studies of individual domains and recent cryoelectron microscopy structures of the full-length enzyme61 show that the structure of the GyrA breakage−reunion domain is a heart-shaped arrangement with two dimer interfaces,62 the CTD displays a spiral six-bladed β-pinwheel structure,63 and the ATP-binding site features a Bergerat64/GHKL fold. This fold is seen in the ATPase domain1,65−71 of a broad family of enzymes such as DNA gyrases, heat shock protein 90 (HSP90), histidine kinase, and MutL and is unrelated to other canonical ATPbinding folds. 64,72 The TOPRIM domain possesses a magnesium-binding site and interacts with the GyrA breakage−reunion domain, forming the catalytic core essential for DNA binding. Combination of structural and biochemical studies of the individual domains has led several authors to suggest a global quaternary structure model and a catalytic mechanism for the holoenzyme (see Figure 2E).73,74 The breakage−reunion domain binds a DNA segment termed the gate or G-segment at the DNA-gate. The N-terminal ATPase domains dimerize upon ATP binding and capture the DNA duplex to be transported (T-segment). The T-segment is then passed through a transient break in the G-segment opened by the breakage−reunion domains, the DNA is resealed and the Tsegment released through a protein gate, the C-gate, prior to resetting of the enzyme into the open clamp form. Concerning the mechanism of action of small molecules inhibiting these enzymes, two classes of inhibitors have been reported so far.

Figure 3. Crystal structure of CcdB−GyrA14 complex (PDB code 1X75). CcdB is dimeric and is represented as pink and magenta ribbons. GyrA14 corresponds to the C-gate (residues 363−494), which is part of the breakage−reunion domain, and is shown in dark blue. The CcdB−GyrA14 complex is superimposed on the breakage− reunion domain of Mycobacterium tuberculosis DNA gyrase (gray).

the C-gate in its closed conformation. Interestingly, shorter peptides, corresponding to the part of CcdBF that interacts with GyrA, were found to also inhibit the DNA supercoiling reaction catalyzed by this enzyme.92 More recently, the chromosomal CcdBVfi protein from Vibrio fischeri was also shown to inhibit DNA gyrase, but the binding mode involved appears to be based on another type of interaction.93 2315


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Figure 4. Structures of microcin B17 (5) and fragment 6.

related to the thiazole−oxazole fragment 28−30, turned out to modestly inhibit DNA gyrase supercoiling activity.111 To conclude this list of peptides, it may be relevant to mention here the so far uncharacterized mixture of polyketidepeptides named albicidins, which have potent antibacterial properties and were isolated from the bacterial phytopathogen Xanthomonas albilineans. Unfortunately, the elucidation of their structures has eluded attempts, although the main component produced was mentioned to have 38 carbons, a molecular mass of 842 Da, and several aromatic rings.112−114 More recent work on the gene cluster responsible for their biosynthesis has shown the presence of polyketide and nonribosomal peptide synthases,114−118 thus suggesting substances made of peptides and polyketides. In any case, this family of compound has recently been demonstrated to selectively and very strongly inhibit bacterial type IIA DNA topoisomerase. They displayed some cross-resistance with quinolone-resistant strains but none with coumarins, thus hinting at action on the catalytic core complex.119 These results, along with the fact that the active fraction is fairly stable and retains an effect at pH 1 for 3 h (but not at pH 10),113 may cause renewed efforts leading to structural elucidation. Concerning the effect of various divalent metals on type IIA topoisomerases, their catalytic properties are strongly dependent on the presence of magnesium salts as a cofactor. As reviewed recently for eukaryotic organisms, all type II topoisomerases require divalent metal ions for their ATPase as well as DNA cleavage activities.120 It was suggested that at least two atoms of magnesium ions per GyrB domain are necessary,121 which was also seen for endonuclease.122 Two reports provide an idea of the essential role of these magnesium(II) ions in the function of type IIA topoisomerases.123,124 By use of manganese(II), it was shown that the GyrB subunit features two binding sites for this metal, the second one also involving DNA along with major conformational changes. As this stoichiometry was also seen for the full enzyme, this pointed out again the plausible participation of a metal in the cleavage−religation activity of the enzyme.123 Moreover, a more recent report described the monitoring of fluoroquinolone-induced DNA cleavage by use of topoisomerase IV featuring mutations in the residues likely to be involved in magnesium ion binding. This study pointed out that the quinolone class of inhibitors, which are known divalent metal chelators,125 may inhibit the type IIA topoisomerases by binding to (or blocking) the accessible surface

Another toxin−antitoxin plasmid system inhibiting DNA gyrase codes for ParE toxin as well as ParD, the corresponding antitoxin.94,95 This ParE protein, which shares only its name with the ParE subunit of topoisomerase IV, when separated from the antitoxin ParD is able to block DNA gyrase,96,97 again leading to cell death for bacteria that do not possess a copy of this plasmid. Recently, based on the 3D structure of the ParD− ParE complex (PDB code 3KXE),98 an attempt to elucidate the binding mode of the toxin ParE to DNA gyrase was made by “deconstruction” of this 12 kDa peptide. Again, a few shorter peptides, featuring a common structural component, retained a capacity to inhibit the DNA supercoiling activity of this enzyme.99 Microcin B17 (5) is a 3.1 kDa, 43-amino-acid bactericidal peptide, produced by E. coli, which, as depicted in Figure 4, is extensively modified post-translationally100 and is classed today in the group of thiazole/oxazole-modified microcin (TOMM). Such peptides are all modified by enzymes from a similar gene cluster,101,102 but their biological activity and actual biochemical targets vary widely.103 Selection of resistant strains could demonstrate that microcin B17 (5) bactericidal effect is mediated by DNA gyrase inhibition104−106 and, as for CcdBF, no effect is seen on topoisomerase IV.107 Moreover, this inhibitor turned out to be less efficient on mutated DNA gyrases, GyrB(K447E) and GyrA(S83W), which are resistant to quinolones, thus implying that its DNA gyrase binding mode is related to these inhibitors.108 Few reports have described biological activity of altered microcin B17 (5).107,109−111 Hydrolysis of the two asparagines (Asn27 and Asn33) into aspartate residues led to a fully inactive compound, thus emphasizing a key role for these two amide residues.110 By altering the sequence of the propeptide leading to microcin B17, analogues featuring an altered number of azole rings were biosynthesized. This pointed out a correlation between the number of rings and the biological effects. Moreover, an essential role for the tandem of oxazole−thiazole systems was illustrated by the fact that an additional pair of such azole rings led to a peptide even more active than microcin B17 (5).109 Various hydrolysis strategies and synthesis of smaller components allowed the evaluation of many microcin B17 fragments. This work confirmed the lack of influence of the nine-residue-long N-terminal glycine chain (Gly4−Gly12) on biological activity and the importance of the C-terminal motif Ser41-His42-Ile43. Moreover, the small thiazol-4-yloxazole 6, 2316


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of the metal inside the enzyme.124 In any case, all these results demonstrate that, in vitro, altering the cellular magnesium concentration or replacing it with other divalent ions is likely to have an effect on the proper functioning of these enzymes as well as on the bacterial growth. 2.3. ATPase Domain Structure

The ATPase domain depicted in Figure 5 is nearly 43 kDa in size and corresponds to the N-terminal part of the B subunit. It is made of two structural subdomains, an N-terminal GHKL domain of about 220 amino acids and a C-terminal transducer domain that contains about 170 residues.76 Most of the crystal structures obtained for the 43 kDa domain are dimers with an N-terminal “strap” of about 14 residues extending into the neighboring monomer to form part of the ATP-binding site (Figure 5, top). A change in the relative positions of the GHKL and transducer domains in response to hydrolysis of ATP126,127 is thought to be important in guiding the transported DNA segment through the cleaved DNA during the catalytic cycle.73 Until now, two conformational states have been described, the ATP-restrained conformation128 observed in the presence of 5′adenylyl-β,γ-imidodiphosphate (ADPNP, 7), a stable ATP analogue, and a relaxed conformation observed in the presence of inhibitors, notably aminocoumarins such as novobiocin (1). The superposition depicted in Figure 5 points out the importance of this structural shift as highlighted by the movement of lysine residue 337, further commented on below. Concerning the binding mode of ADPNP (7), as depicted in Figure 6, the DNA gyrase and topoisomerase IV structures (respectively PDB codes 1EI1129 and 1S16130) show that the molecule lies on the N-terminal top of the α6-helix and faces the α4-helix (see the sequence alignment in the Supporting Information). Most residues at the ATP-binding site come from the GHKL domain. A conserved glutamate (Glu42 in E. coli) has been suggested to be the catalytic base that removes a proton from a water molecule, which then attacks the γphosphate of the ATP. A glycine-rich loop (residues 99−120 with a GxxGxG motif) or “ATP-lid” surrounding ADPNP (7) consists of Gly114, Gly117, and Gly119 (E. coli GyrB numbering), whose nitrogens point toward the phosphates of ADPNP (7). This loop adopts a closed conformation upon ATP binding and is associated with the ATP-restrained conformation, in contrast with the open conformation adopted in the presence of other inhibitors. Lys103 has been suggested to have a role in enzyme conformational changes and/or in the coupling of ATP hydrolysis131 and forms a salt bridge with an oxygen on the β-phosphate of ATP. In addition, a lysine residue (Lys337 in E. coli), belonging to a conserved motif in the Cterminal region (QTK) from the transducer domain, contacts the γ-phosphate. This “switch lysine” is thought to couple the hydrolysis of ATP to the relative movement between the GHKL and transducer domains.73 Furthermore, a tyrosine (Tyr5 in E. coli) from the N-terminal “strap” interacts with ADPNP (7), forming hydrogen bonds with the 2′-hydroxyl of the ribose and the N3 of the adenine. On the opposite side, Asp73 forms a hydrogen bond with the N6 of the adenine.

Figure 5. Structure of ATPase domain of bacterial type IIA topoisomerases. (Top) The ATPase domain is dimeric and made of two structural subdomains, the N-terminal GHKL domain of about 220 amino acids (in yellow) and the C-terminal transducer domain that contains about 170 residues (in orange). ADPNP is shown in red. The second protomer is represented in gray with ADPNP in black (PDB code 1EI1). (Bottom) Superimposition of the two conformational states, the ATP-restrained conformation (in pale yellow) observed in the presence of ADPNP (in red) (PDB code 1EI1) and a relaxed conformation observed in the presence of novobiocin (in black) (PDB code 1KIJ); the “switch lysine” (Lys337) is shown in cyan and green, respectively.

3. ASSAYS FOR BACTERIAL TYPE IIA TOPOISOMERASE INHIBITION The biochemical assays for these enzymes have been the recent focus of a case study for structure-based drug discovery programs.132 DNA-based assays, which monitor its alterations, have also been reviewed.133 Concerning the latter type of assay,

for DNA gyrase, it measures ATP-dependent supercoiling of a relaxed circular plasmid, and for topoisomerase IV, it assesses 2317


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different phenotypic assay, based on luciferase expression driven by a promoter response to DNA damage, was shown to efficiently detect the strand breaks caused by representative fluoroquinolones.145 In another whole-cell approach, two lines of bacteria differing only in the level of expression of, for instance DNA gyrase, are monitored for growth inhibition in the presence of compounds. A lesser effect on the growth of the high-expressing strain indicates a plausible action of the compound on DNA gyrase.146 To monitor the consumption of ATP by these topoisomerases, the ammonium molybdate/ malachite green-based assay,147 which measures the release of mineral phosphate at 620 nm, has been used for highthroughput screenings.148−151 This mineral phosphate release can also be assessed by use of 7-methyl-6-thioguanosine and purine nucleoside phosphorylase, which leads to the occurrence of a product with increased absorbance at 360 nm.132,152,153 The binding of tritium-labeled [3H]dihydronovobiocin to a biotin-labeled 43-kDa fragment of GyrB (biotin−GyrB43) was used as an assay amenable to high-throughput screening for DNA gyrase inhibitors.154 Fluorescence polarization-based assays are also possible since derivatization, with a fluorescent component, of known inhibitors can provide probes that retain an affinity for the type IIA topoisomerases. A high-throughput fluorescence polarization assay for inhibitors of the DNA gyrase ATPase domain was thus designed with the use of the novobiocin-derived probe novo-TRX (8)155 depicted in Figure 7. Many examples of fluorescent groups are claimed in the

Figure 6. (Top) Chemical structure of ADPNP (7). (Bottom) Canonical structure of GHKL domain of bacterial type IIA topoisomerase in complex with ADPNP (in red). GHKL domain is represented in yellow ribbon format (PDB code 1EI1). The α6-helix is represented in salmon and the α4-helix in wheat. Tyr5, Glu42, Asp73, Lys307, and Lys337 are shown in black stick format. The loop that contains the Lys337 is represented in orange and the ATP-lid in green. The N-terminal strap of the neighboring protomer is shown in gray. The structure of GHKL and the ATP binding mode are very similar for DNA gyrase and topoisomerase IV. For better clarity, Ser5 of the PDB structure 1EI1, which is a mutant of the E. coli DNA gyrase wild type, has been modeled as a tyrosine, which is highly conserved in DNA gyrases and topoisomerases IV.

ATP-dependent decatenation of kinetoplast DNA. Moreover, DNA cleavage assays can be used for both types of enzymes. A patent describes a process, amenable to high-throughput screening, to measure the occurrence, upon inhibition, of immobilized covalent topoisomerase−DNA adducts.134 Another high-throughput assay was designed with the use of a fluorescent nucleic acid stain that has a different affinity for relaxed or supercoiled DNA.135 A Bodipy-FL-labeled oligonucleotide (i.e., TTCTTCTTC) has been used as a probe for high-throughput supercoiling monitoring.136,137 This probe, which preferentially binds to relaxed double-stranded plasmid containing the triplex-forming sequence (TTC)9 in comparison with the corresponding supercoiled plasmid, was also reported more recently to be useful for assessing the supercoiled DNA relaxing activity of topoisomerase IIα, one of the two human type II topoisomerase isoforms.138 Such detection of supercoiled DNA via the formation of immobilized triplex species was also adapted to the design of high-throughput assays.139−141 The supercoiling degree of plasmid could also be determined by use of luciferase as a reporter gene.142 Since DNA gyrase inhibitors induces an SOS response in Bacillus subtilis, genetically altered stains were designed to be used as a whole-cell assay for such compounds.143 Another whole-cell assay, the anucleate cell blue assay based on chromosome partitioning in E. coli, was also demonstrated to efficiently detect inhibitors of bacterial type IIA topoisomerases.144 A

Figure 7. Structure of novo-TRX (8).

corresponding patent156 and a second polarization assay, using the so far undisclosed fluorescent probe MT3-192, has also been mentioned for the same enzyme.132 Finally, a patent has described a process for monitoring the inhibition of DNA gyrase activity by using isothermal titration calorimetry as well as the appearance (or not) of a temperature gradient between control and test wells.157

4. NON-QUINOLONE INHIBITORS OF TYPE IIA TOPOISOMERASES 4.1. Aminocoumarin-Containing Compounds: The First Class of DNA Gyrase ATPase Inhibitors

Novobiocin (1)158−162 and other 3-aminocoumarin-containing compounds such as coumermycin A1 (9)163,164 and clorobiocin (10),165 depicted in Figure 8, belong to a class of naturally occurring antibiotics, produced by Streptomyces strains, that inhibit bacterial type IIA topoisomerases. As mentioned above, 2318


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demonstrated potentially useful activity in vitro.185,186 However, the strong serum binding of this large molecule has been advanced as the cause of its lack of effect in vivo.187 Extensive studies of the antibacterial mechanism of action of novobiocin (1) and coumermycin A1 (9) demonstrated that they inhibit DNA gyrase and topoisomerase IV by binding to the ATPase domain of GyrB and ParE subunits, respectively.7,8,70,181,188−190 A third naturally occurring coumarin, clorobiocin (10), features a structure closely related to novobiocin (1) but for a pyrrole moiety replacing the carbamate group and a chlorine atom instead of a methyl. This compound was also the focus of medicinal chemistry research programs further described in the following. As depicted in Figure 9, the crystal structures of the ATPase domain, or the GHKL subdomain, in complex with two aminocoumarins, novobiocin (1) (PDB code 1KIJ)191 and clorobiocin (10) (PDB code 1KZN),192 revealed that these molecules lie at the entry of the ATP-binding site. These inhibitors thus overlap the position occupied by the adenine ring of the ATP molecule with their novobiose group. The strongest interaction between these coumarins and the ATPbinding site is mediated by the Asp73 residue. Indeed, a network of hydrogen bonds is seen between Asp73, a resident water molecule, and the carbamate group of novobiocin (1) or the carboxypyrrole of clorobiocin (10). With these two cases, the notion of bioisosterism is actually quite well illustrated. Moreover, as the pyrrole ring of clorobiocin (10) also features a methyl, this pointed out the existence of a potentially useful lipophilic pocket not occupied by novobiocin (1). Indeed, this methyl group, along with the two water molecules expelled by the pyrrole ring, explains the rather stronger affinity of clorobiocin (10) for DNA gyrase.192 Another interaction is seen between the conserved Arg136, localized at the entry of the ATP-binding pocket, and the carbonyl oxygen of the coumarin ring system. In addition, a salt bridge between residues Glu50 and Arg76 forms a portion of the novobiocin binding pocket. This salt bridge has been shown to be important for novobiocin binding as well as for the ATPase activity.131 From these aminocoumarins, following early attempts,193−196 medicinal chemistry programs were undertaken in the late 1990s in order to alleviate the shortcomings of this series.197−204 The level of antibacterial activity of the 2thioimidazo derivatives 11 and 12, depicted in Figure 10, pointed out that the polar and poorly soluble amide function on position 3 of the coumarin ring could be removed, depending on the substituents at position 4.198,203 However, isothermal titration studies pointed out a subtle role for the hydroxybenzoate isopentenyl moiety by “accommodating” clorobiocin (10) into the ATP binding site.192 Interestingly, a methyl on position 4 also provided good activity for a 3carboxylic acid derivative, and a similar effect was seen with a lipophilic cyclohexyl group on carbon 5.200 If an acetic acid group on position 4 was detrimental to activity,200 the phosphonate derivative RU64135 (13) and the demethylated rhamnose-containing analogue 14 were of interest.192 Reverse amides such as 15 and 16 were also found to be very active, including on novobiocin-resistant bacterial strains.199 If the replacement of novobiose by rhamnose only led to less active analogues,200 the search for other mimics pointed out the crucial role of the novobiose methoxy substituent.197,204,205 This was also confirmed in the course of isolation and evaluation of analogues obtained by mutasynthesis.206 Surpris-

Figure 8. Structures of coumermycin (9) and clorobiocin (10).

they competitively inhibit the energy transduction of these enzymes by binding to their ATPase active sites. Novobiocin (1) underwent a series of clinical trials in the 1950s either parenterally or per os.166−170 This led to its commercialization, by Upjohn, in the United States and elsewhere for many years, either in combination with tetracycline (panalba) or as the sole active component (albamycin). The eventual withdrawal, of the combination (panalba) from the U.S. Pharmacopoeia took place in 1970 and its proceeding is probably of historical value on the subject of relationship between pharmaceutical interests and a country health authority.171,172 Later clinical trials with novobiocin (1) either alone173,174 or in combination with rifampin175 focused on the eradication of antibiotic-resistant bacterial strains. Moreover, the use of novobiocin (1) to fight catheter infection has also been considered.176,177 The actual manufacturing of albamycin-T was discontinued only in 1999 and, as recently as 2011, the U.S. Food and Drug Administration (FDA) was driven to issue a public notice concerning its medical value.178 In this notice, it is stated: “The literature and adverse event reports [on novobiocin] reveal several significant safety concerns. Reported adverse reactions include relatively common skin reactions, jaundice, hepatic failure, and blood dyscrasias (neutropenia, anemia, and thrombocytopenia). The literature also reveals concern about the development of novobiocin-resistant staphylococci during treatment, and a potential for drug interactions. In light of the significant safety concerns with this product, we conclude that the withdrawal of this product from the market was on the basis of safety or effectiveness.”178 Few primary data on the pharmacokinetics of novobiocin are available:179 its plasmatic half-life was reported to be between 1.7 and 4 h, and serum concentration level of 50−100 mg/L could be achieved after repeated doses.180 An earlier review mentioned its poor solubility and low activity against Gram-negative bacteria as well as toxicity toward eukaryotes.181 The lack of activity on Gram-negative bacteria could be ascribed to this low solubility. Moreover, the many effects of novobiocin (1) in models of biochemical processes, such as histone precipitation,182 inhibition of yeast glycyl- and leucyl-tRNA synthetases,183 eukaryotic topoisomerases,182 or HSP90,184 probably explain the eukaryotic toxicity of such compounds.180 Coumermycin (9) was also the subject of studies across the years as it 2319


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Figure 10. Structures of 11−18.

Following these synthetic endeavors, extensive work on the genes involved in the biosynthesis of these aminocoumarins was undertaken.209 Genetic alteration and/or combination of some of these enzymes led to the isolation of many analogues obtained by mutasynthesis.206,210−218 The resulting structure− activity relationships for these analogues were reviewed across the years.219,220 One of the prominent results of all this work is the isolation of analogue 18, featuring a 3,4-dihydroxybenzamide group; along with a strong effect on DNA gyrase, 18 shows a good level of antibacterial activity.217 It appears that its 3,4-dihydroxybenzamide group is recognized by the catechol transporters present on E. coli membrane, thus securing active transport for this otherwise poorly soluble inhibitor. Unfortunately, the 3,4-dihydroxybenzamide group of 18 is not an encouraging feature for a pharmacological profile, as it will be very likely prone to glucuronidation leading to quick excretion in vivo. Further work on isolation of naturally occurring antibiotics led to the coumabiocins, a series of coumarincontaining analogues of novobiocin in which the prenyl group has undergone cyclization with the phenol function to lead to benzopyran or benzofuran derivatives.221

Figure 9. (Top) Zoomed-in view of binding mode of novobiocin (1) (in magenta) in the ATPase domain of Thermus thermophilus DNA gyrase (PDB code 1KIJ). Asp73, Glu50, Arg76, and Arg136 are represented in stick format. The two expelled and the resident water molecules are shown as red spheres. Hydrogen bonds are represented by black dashed lines. The orientation is rotated about 180° parallel to the plane of the figure when compared to Figure 6. (Bottom) Zoomed-in view of binding mode of clorobiocin (10) (in orange) in the ATPase domain of E. coli DNA gyrase (PDB code 1KZN) in the same orientation.

ingly, in view of the structures of more recent inhibitors, very few attempts to replace the coumarin ring with other heterocyclic systems were undertaken/reported. One approach used a 1,2-benzooxathiin 2,2-dioxide ring and led to active analogues in a biochemical test. However, these compounds had too strong and inherent polarity to be effective against bacterial growth.207 Finally, the optimized spiro derivative RU79115 (17) resulted from the preparation of analogues featuring extensive alterations of the novobiose system,202,208 including the introduction of a substituted carbamate as a pyrrole bioisostere.201 Apparently, further pharmacological evaluation of 17 was unfortunately not successful. The two reactive N−O bonds present in this structure may be at the source of this, although nothing was reported in the literature.

4.2. Cyclothialidines: The Second Class of DNA Gyrase ATPase Inhibitors

Cyclothialidine (19), another naturally occurring compound depicted in Figure 11, was discovered in the course of a DNA gyrase inhibition screening of fermentation broth of Streptomyces NR0484 FERM-BP-1982.222−226 The closely related analogue GR122222X/cyclothialidine C (20) was also isolated by another research laboratory,227 and additional derivatives lacking a methyl on the resorcinol ring or featuring a glutamic 2320


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be the most active in vivo with an ED50 of 3 mg/kg in a mouse model of septicaemia.235 Glucuronidation of the essential phenol group, leading to fast elimination in vivo, was also mentioned as a concern for this series of inhibitors.231 This was probably another aspect to manage along with the delicate balance between lipophilicity and in vivo efficacy. Indeed, as the chosen lipophilic bromine atom of 25 influences the acidity of the phenol function, it is possible to suggest that this alteration also had a beneficial effect on its glucuronidation incidence.235 Many seco analogues of cyclothialidine, such as 26 and 27, were also found to be active in vitro.231,233 However, these lipophilic analogues (the logP of 27 is 3.1) showed only minor effects in vivo in a mouse sepsis model.233 Finally, a few other resorcinol-containing compounds have been reported to modestly inhibit DNA gyrase.236

Figure 11. (Top) Structures of cyclothialidines 19 and 20. (Bottom) Zoomed-in view of binding mode for GR122222X/cyclothialidine C (20) with ATPase domain of E. coli DNA gyrase in the same orientation shown in Figure 9

acid residue instead of the serine of cyclothialidine have been reported.228 The X-ray structure of cyclothialidine C (20) in complex with the GHKL subdomain of E. coli DNA gyrase (the PDB file used to produce Figure 11 was kindly provided by Professor D. B. Wigley)229 further confirmed that this inhibitor also occupies part of the ATPase catalytic site.230 Interestingly, cyclothialidine C (20), contrary to the coumarins (see Figure 9), is wrapped around the α4-helix. As a consequence, no stacking interaction is observed between the Glu50−Arg76 salt bridge and cyclothialidine C (20). The Asp73 residue and its resident water molecule interact with the resorcinol ring of this inhibitor, and the Arg136 residue binds with the peptidic part (the alanine moiety). Although cyclothialidine (19) essentially lacks an effect on bacteria featuring an intact cell wall,231 the encouraging in vitro activity of early analogues,222 along with the absence of mammalian topoisomerase inhibition, led to extensive structure−activity studies.228,231−235 It quickly became clear that the peptidic side chain of the macrocycle of this compound did not provide favorable in vitro antibacterial properties. Indeed, as seen in Figure 11, this part of the cyclothialidine does not interact much with the ATP-binding pocket. A process of structural alteration led to analogues such as 21−24, which included an essential phenol function, a lipophilic thioamide, and an oxadiazole component. Interestingly, analogues 21 and 22 displayed good antibacterial activity, but these were disappointing in vivo. On the other hand, the more hydrophilic hydroxymethylated derivatives 23 and 24, although less active in vitro by a factor of 8, had an ED50 of 8−12 mg/kg in a mouse model of septicemia.231 Further insights in this balance between lipophilicity and in vivo efficacy led to the lactam−lactone derivative 25, which also features a lipophilic bromine group and avoids a thioamide function. This compound turned out to


4.3. More DNA Gyrase ATPase Inhibitors: A Feat of Bioisosterism

As depicted in Figure 13, the X-ray-based structures of the “historical” inhibitors237 bound to the ATP-binding pocket of DNA gyrase demonstrated that the carbamate of novobiocin (1), the 2-carboxypyrrole of clorobiocin (10),238 and the phenol function of cyclothialidine C (20)229, as well as the aminopurine portion of ADPNP (7), are bioisosteres able to interact with the Asp73 residue and its resident water molecule. From these observations, what are called today fragment-based drug design campaigns were initiated. Accordingly, a list of small molecules featuring a donor−acceptor motif effectively binding Asp73 were reported,239 and more recently, a virtual approach provided even more potential fragments.240 The quite limitless series of DNA gyrase ATPase inhibitors that are described in the following is probably a good illustration of the value of this approach, although more traditional screening campaigns were also major contributors to this list. Among early examples of fragment-based design, the weak effect on DNA gyrase of the phenol derivative 28,239 along with the structural data depicted above, led to the tetracyclic antibacterial 31, which, contrary to other analogues of 31, was devoid of cross-resistance with novobiocin (1).241 This discovery process took place by increments, via the synthesis 2321


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Concerning the residue numbering adopted, Table 1 provides the conversion between E. coli numbering and that of other Table 1. Conversion between Residue Numbering species and protein

Asp

Arga

Glua

Argb

Asn

E. coli GyrB T. thermophilus GyrB E. coli ParEc E. coli ParEd X. oryzaee ParE S. aureus GyrB E. faecalis GyrB E. faecalis ParE M. smegmatis GyrB F. tularensisf ParE S. pneumoniae ParE

73 72 1069 69 113 81 82 76 79 68 78

76 75 1072 72 116 84 85 79 82 71 81

50 49 1046 46 90 58 59 53 56 45 55

136 135 1132 132 176 144 145 138 141 131 140

46 45 1402 42 86 54 55 49 52 41 51

a

These residues form a conserved salt bridge. bThis residue is sometimes replaced by lysine. cNumbering for the structure with PDB code 1S14. dNumbering for the structure with PDB code 3FV5. e Xanthomonas oryzae. fFrancisella tularensis.

species for key conserved residues of the GyrB and ParE ATPase domain, which we have used in all our comments. Moreover, an extensive and potentially useful sequence alignment for the GyrB and ParE ATPase domains of many species is provided in Supporting Information. We also list in this section all the X-ray structures reported with a depiction of the corresponding inhibitor bound. Moreover, the original pictures of many of these inhibitors embedded in the ATPbinding site, which were often much larger than could be shown in this review, can be also found in Supporting Information. A fragment-based NMR screening strategy recognized the potential of the carboxypyrrole moiety seen in clorobiocin (10). This led to the design of pyrrole libraries and to amides 32, which turned out to inhibit E. coli DNA gyrase at the micromolar level.242 From the X-ray structure of 32 bound to the ATP-binding pocket of S. aureus DNA gyrase (PDB code 3U2D), medicinal chemistry iterations led to 33, which, due to additional interactions provided by the chlorine atoms on the pyrrole ring, was 150-fold more potent. The X-ray structure (PDB code 3U2K) of 33 depicted in Figure 14 illustrates these additional interactions. The two chlorine atoms of the pyrrole ring not only occupy a lipophilic pocket but also increase the acidity of the pyrrole hydrogen, thus improving its interaction with the Asp73 residue, while the carboxamide of the pyridine ring interacts with the Arg136 residue.242 The acid-bearing pyrrole amide 34, subsequently made, also displayed an effect in vivo on a mouse model of S. pneumoniae infection.243 Further medicinal chemistry led to the optimized amide 35, which displayed significant antibacterial activity.242−244 As shown in Figure 15, X-ray analysis (PDB code 3TTZ) of the binding mode of 35 pointed out that aside from a 2-carboxypyrrole system interacting with the Asp73 residue, the additional interaction with Arg136 was secured with the carboxylic acid function of the thiazole ring. Moreover, introduction of a fluorine group on the piperidine ring of 35 also helped to bind the GIP pocket (see sequence alignment in Supporting Information), a hydrophobic area made by the highly conserved Ile78 and Ile94 residues. This fluorine actually improved the affinity of 35 for the ATP-binding site by more than an order of magnitude in comparison with 34 and the in

Figure 13. (Top) Interactions of 1, 10, 20, and 7 with GyrB Asp73. Only a fragment of GHKL subdomain is represented (β3-strand and β3-α5-loop that contains Arg76; see alignment of bacterial type IIA topoisomerase sequences in Supporting Information). (Bottom) Four stages of fragment-based drug design.

and evaluation of bigger and bigger fragments incorporating structural features known (by X-ray or from structure−activity relationships obtained for other series) to have an affinity for the DNA gyrase ATP-binding site. For instance, the “structural path” that led to inhibitor 31 went through iterations of synthesis and evaluation of key compounds such as 29 and 30. However, many other “intermediates” were made in this work and it is, of course, the sum of the accumulated knowledge that led to the optimized inhibitor 31. Thus, the only apparent limit in such iterative processes is (has it ever been otherwise?) the chemistry found to be possible around a fragment. The structural data are also very useful, as they are essential in orienting and shortening the number of such synthesis/ evaluation iterations. However, past the stage of finding good inhibitors in vitro, extensive work is then required to retain an effect in cellulo and then in vivo. For instance, in the case of 31, the bromine atom was shown to be essential to provide promising activity against Gram-positive bacteria.241 However, apparently this series was not further pursued, conceivably for a lack of activity in vivo caused by a fast glucuronidation of the phenol moiety. In the following, we have, as much as possible, classed the series of inhibitors of the ATPase activity according to structural motifs binding the E. coli DNA gyrase Asp73 residue. Providing, for every series, all the elements that led to the optimized inhibitors listed here is, however, beyond the scope of this review. We have tried to illustrate some of the recurrent issues, along with the solutions found, by depicting the structural data describing the interaction of these inhibitors with the DNA gyrase and topoisomerase IV ATP-binding site. 2322


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Figure 14. (Top) Structures of 32 and 33. (Bottom) Zoomed-in view of binding mode for 33 (in green) with GHKL subdomain of S. aureus DNA gyrase (PDB code 3U2K).

vivo efficacy by a factor of 4, with an ED50 of 54 mg/kg.243 Cross-resistance experiments pointed out that strains resistant to 34 were also impervious to other analogues, with the notable exception of the amide-bearing derivative 33, which retained an effect on the S. pneumoniae GyrB Lys136Ile mutated strain. Note: as mentioned in Table 1, in the case of streptococci the wild-type residue in this position is not an arginine but a lysine.244 Other analogues, featuring larger245 or smaller246−248 aminated rings instead of the central 4-aminopiperidine, have also been claimed. Moreover, very active DNA gyrase inhibitors featuring an additional heterocyclic ring and a fluorine or a methoxy moiety as seen in 36−40 have also been claimed.249−251 The triazole-bearing compounds 38 and 39 were specifically studied for their antimycobacterial properties252 and were recently reported to be modestly effective in vivo in chronic and acute murine models of M. tuberculosis infection.253,254 The recourse to a triazole group seen in 38 and 39 did not alter the good solubility of this series but improved the pharmacological profile in mice. It was suggested that the bulk of this group protects the acid function from extensive glucuronidation.254 The spontaneous frequency of mutation on M. tuberculosis was also assessed for these compounds. It was found to be typical of the inhibition of a single biochemical target, and unfortunately M. tuberculosis features a single type IIA topoisomerase.254 A series of bicyclic analogues incorporating the pyrrolamide motif, such as 40, which displayed an IC50 of 50 ng/mL on S. pneumoniae, was also claimed.255 Remarkably, the 3,4-dichloropyrrole motif seen in 34−37 is sometime found in a series of far more complex naturally occurring antibiotics,256−261 such as the diastereoisomers kibdelomycin/amicolamycin (41). Recently, these antibacterials were indeed reported to inhibit the ATPase function of type IIA bacterial topoisomerases.259,260 Finally, a bioisosteric switch from the pyrrole ring of compounds 32−39 to an imidazole

Figure 15. (Top) Structures of 34−42. (Bottom) Zoomed-in view of binding mode for 35 (in cyan) with GHKL subdomain of S. aureus DNA gyrase (PDB code 3TTZ) in the same orientation shown in Figure 14.

was successful, and many antibacterials such as analogue 42 have also been patented.262 The triazine series of inhibitors of the ATPase function of DNA gyrase, illustrated in Figure 16 by 43−45, were found by a random reporter-gene-based screening. Concerns about a nonspecific antibacterial effect, due to an inhibition of the bacterial oxygen uptake for the most lipophilic derivative, oriented the medicinal program toward the synthesis of hydrophilic analogues.205 And indeed, the (unavailable) Xray-derived structure of the more soluble derivative 44, featuring an ammonium moiety, embedded in the GHKL subdomain of DNA gyrase provided information on its binding 2323


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pyridyl moiety and the positively charged component of the Glu50−Arg76 salt bridge, and (iii) the imidazole ring reaching into a hydrophobic area made by an array of valine residues. A pharmacophore-based screening265−267 led to the pyrrolo[2,3-d]pyrimidine 49, which turned out to be a very weak Enterococcus faecalis GyrB inhibitor. This heterocycle was identified by a fragment-based crystallographic screening that sought original heterocycles featuring a hydrogen-donor/ acceptor tandem binding the Asp73 and its structural water. Extensive medicinal chemistry, along with X-ray crystallographic studies, gave good inhibitors such as 50. As depicted in Figure 17, the X-ray structure of this compound bound to E. faecalis GyrB (PDB code 4HXW) pointed out the interactions of the pyrrolo[2,3-d]pyrimidine with Asp73 and a notable

Figure 16. (Top) Structures of 43−48. (Bottom) Zoomed-in view of the binding mode for 48 with GHKL subdomain of E. coli DNA gyrase (PDB code 4HYP) in the same orientation as in Figure 14. Conserved Val43, Val71, Val124, and Val171 are represented in gray stick format.

mode.205,263 In this case, one of the triazine nitrogen acts as the acceptor of the bound water molecule, while the amine function interacts directly with the Asp73 residue. Further work on this series led to the aminotriazine 45 bearing an acidic 4hydroxycoumarin, which played a role similar to the one found in novobiocin (1), an interaction with the Arg136 residue. Again the lipophilicity was a crucial factor governing the antibacterial activity in this series, and 45, although a fairly strong inhibitor of DNA gyrase, displayed only a modest effect on S. aureus growth.205 From the nature of the interactions between the ATP-binding pocket and the purine ring of ADPNP (5) or the triazines 43−45, the “rescaffolded” 4aminopyrazolo[3,4-d]pyrimidine 46 was also discovered. The benzoic acid present in the structure of 46 turned out to also reach for the Arg136 residue, although replacing this component with a 4-hydroxycoumarin was equally possible.264 Very recently, the structures of thiazolo[5,4-d]pyrimidine derivatives 47 and 48 bound respectively to E. coli ParE (PDB code 4HZ0) and GyrB (PDB code 4HYP) were deposited in the Protein Data Bank.265 As depicted in Figure 16, 48 binds the GHKL subdomain by (i) an interaction between the hydrogen donor and acceptor pairing made by the aminopyrimidine ring and the tandem made by Asp73 and a resident water molecule, (ii) a π-cation bond between the 3-

Figure 17. (Top) Structures of 49−55. (Bottom) Zoomed-in view of the binding mode for 50 with GHKL subdomain of E. faecalis DNA gyrase (PDB code 4HXW) in the same orientation shown in Figure 14. Conserved Asn46 is also represented in stick format. In E. faecalis DNA gyrase, the Arg136 is replaced by Lys. 2324


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contact of the primary amine with the highly conserved Asn46 residue and an ordered water molecule. Moreover, there is a π− cation interaction between the azanaphthyridine and the Glu50−Arg76 salt bridge. The optimized compound 51, which inhibited at the nanomolar level an array of bacterial DNA gyrase or topoisomerase IV enzymes, features a naphthyridine ring optimal for this π−cation interaction with the Glu50−Arg76 salt bridge. Replacement of the naphthyridine ring of 51 with a quinoline, as depicted for 52, led to an important loss of activity, thus illustrating the importance of this nitrogen for good interaction with this salt bridge. Finally, the rigid azabicyclo[3.1.0]hexane scaffold was optimal in orienting the primary amine function of 51 toward the conserved Asn46 residue and an ordered water molecule.265,267 Interestingly, contrary to a hydroxyl, such primary amine function also greatly improved the activity on Gram-negative bacteria.267 An extensive evaluation of this type of inhibitors pointed out that 51 displayed an encouraging lack of crossresistance along with micromolar level of effect against strains of Pseudomonas aeruginosa, including a resistant one.268 The same research group has also patented tricyclic inhibitors such as 53. The depicted X-ray derived binding mode of 53 to the E. faecalis DNA gyrase ATP-binding pocket is provided in the patent, which sums up the knowledge accumulated in the course of 17 different structures of inhibitor−GyrB complexes.269 As for 50 and 51, the rigid scaffold sporting a primary amine seen in the structure of 53 is probably instrumental to reach the conserved Asn46. The forthcoming structures (PDB codes 4K4O, 4KFG, 4KQV, 4KSG, 4KSH, and 4KTN) to be deposited in the Protein Data Bank, along with future publications, will probably provide more detailed insights on the subject. The frequency of spontaneous mutation was determined on E. coli for compounds such as 53. The very low value obtained for these dual inhibitors of DNA gyrase and topoisomerase IV were correlated with strong inhibition of the ParE subunit of topoisomerase IV.270 Another research group has recently reported a series of 4,5′-bisthiazole inhibitors featuring an amide function. This series was obtained by virtual screening of about 5 million commercially available compounds, followed by biochemical confirmation and crowned by the X-ray-determined binding pattern (PDB code 4DUH) schematically depicted for 54.271 Interestingly, analogues such as the closely related 55 have been claimed as inhibitors of the human phosphoinositide 3-kinase γ with an IC50 on this enzyme of 10 nM.272 This kinase is a class I kinase and is thus devoid of a GHKL fold for its ATPase domain. Another extensively studied series of dual DNA gyrase/ topoisomerase IV inhibitors includes compounds such as 56− 67 characterized by an ethylurea side chain. Following one early structure of such an inhibitor bound to the ATP-binding site of topoisomerase IV (PDB code 3FV5), four more should be released very soon (PDB codes 4MBC, 4MB9, 4LPO, and 4LPB). As depicted in Figure 18 for 56,273 its cocrystallization with the GHKL domain of E. coli topoisomerase IV (PDB code 3FV5) pointed out the interaction of Asp73 residue with two hydrogens of the urea group as well as Arg136 residue with the 3-pyridyl group. The imidazole component of the benzimidazole scaffold of 56 is instrumental in orienting correctly the urea side by an intramolecular hydrogen bond. Moreover, the ketone moiety is also important, as the imidazole hydrogen is thus trapped in the depicted tautomeric form. For VRT-752586 (57), the combination of urea side chain and two pyridine substituents was found optimal for an effect, either intra-

Figure 18. (Top) Structures of 56−58. (Bottom) Zoomed-in view of binding mode of 56 with GHKL subdomain of E. coli topoisomerase IV (PDB code 3FV5) in the same orientation shown in Figure 14. The intramolecular hydrogen bond observed in 56 is also represented.

venously or orally, in rodent models of skin infection or pneumonia.273−275 Interestingly, the amide function of 58 could be introduced instead of the 3-pyridyl group seen in 56 and 57.273 Thus, the ketone function of 56, the 2-pyridyl of 57, and the 1-pyrazoyl group of 58 are equally able to freeze the benzimidazole in the tautomeric form depicted. Many more analogues have been made, and as depicted in Figure 19, even with a lack of possible tautomerism, the analogue 59, featuring a [1,2,4]triazolo[1,5-a]pyridine ring,276,277 or the benzo[d]thiazole derivatives 60 and 61278−280 and aza analogues,281 as well as the imidazo[1,2a]pyridine 62,282 are also good inhibitors. Concerning the dual DNA gyrase/topoisomerase IV inhibitors 60 and 61, their in vitro and in vivo evaluation were the subject of a recent report.283 In cellulo, this dual inhibition actually provided 60 and 61 with a frequency of spontaneous resistance 2 orders of magnitude lower in S. aureus than the one observed for novobiocin (1). A strong profile against Gram-positive bacteria was seen. In contrast, 60 and 61 were inactive against the majority of Gram-negative species. Pharmacokinetic studies in rats pointed out superior parameters for 61 in comparison with 60, thus pointing out the importance of the α-substitution pattern for the carboxylic moiety. More rescaffolding of these ethylurea derivatives led to imidazo[1,2-b]pyridazine 63,284 thiazolo[5,4-b]pyridine 64,285 or isoquinolin-3-yl derivatives such as 65.286 Concerning thiazolo[5,4-b]pyridines such as 63, extensive preclinical data focusing on tuberculosis were reported recently.287 This work pointed out some efficacy of 64 at the dose of 300 mg/kg in an acute murine model of tuberculosis. Moreover, the assessment of the spontaneous mutation frequency pointed out a value (3.1 × 10−8) characteristic of single enzyme targeting. Unfortunately, M. 2325


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place with the complete enzyme since, so far, all the crystals obtained used only the GHKL subdomain of ParE. The relatively low spontaneous mutation frequency found in S. aureus pointed out again the benefit of dual inhibition of DNA gyrase and topoisomerase IV by 67. Moreover, in vivo, against a S. aureus neutropenic mouse thigh infection model, an EC50 of 200 mg/kg was found for this compound. However, an issue of low solubility (19 μM for 67) is mentioned for this series of analogues.293 Finally, an array of recent patents294 specifically claiming the preparation and use of the two optically pure tetrahydrofuran derivatives 68295 and 69,296 featuring a tertiary alcohol or the corresponding phosphate prodrugs,297 are encouraging clues concerning future clinical development for this series. Among extensive preclinical studies, at oral doses of up to 100 mg/kg, in vivo efficacy in a mouse S. aureus kidney infection model was demonstrated for the dual DNA gyrase/ topoisomerase IV inhibitor 69.294 Apparently, the issue of low solubility associated with high protein binding, recurrent with this class of inhibitors, was addressed in the course of design of 68 and 69 or their phosphate prodrugs.298 Interestingly, alcohol derivatives as well as the corresponding phosphate prodrugs related to 60 and 61 were the subject of a very recent patent.280 The vast number of different groups capable of interaction with the Arg136 residue is also well illustrated in the structures of 56−69. Provided that a correct orientation is achieved, it appears that basic or acidic moieties are possible within this series. Taking into account the eventual importance of a Glu50−Arg76 salt bridge, which is prone to a π−cation interaction with this part of the inhibitors,239,265,267 should provide further explanations for some of the structure−activity relationships in this class of inhibitors. In this regard, the difference of interactions with the Arg136 residue and the Glu50−Arg76 salt bridge seen, in the X-ray structures (PDB codes 4LPO and 4LBP), for 66 and 67 is an illustration of the difficulties that could be encountered in any predictive approach. By use of virtual fragment-based screening, a possible bioisosteric replacement with the virtual pyrrolo[2,3-b]pyridine derivative 70 was suggested. As depicted in Figure 20, the X-ray structure of the weakly active carboxy-bearing derivative 71 bound to the GHKL domain of S. pneumoniae topoisomerase IV (PDB code 4EM7), proved that this heterocycle provides the hydrogen donor−acceptor pair interacting with the Asp73 residue and its ordered water molecule.299 Moreover, as the virtual hit 70 is devoid of activity, the carboxylic acid of 71, which interacts with the Arg136 residue, along with a π−cation interaction with the Glu50−Arg76 salt bridge, is instrumental in the modest biochemical effect observed (IC50 of 7.7 μM on S. pneumoniae ParE). Adding an N-ethyl carboxamide, very reminiscent of the N-ethylurea derivatives 56−69 described above, along with an array of other substituents on the core heterocycle led to the optimized compound 72 (IC50 of 0.005 μM on S. pneumoniae ParE). As depicted, the X-ray structure of 72 bound to the GHKL domain of S. pneumoniae topoisomerase IV (PDB code 4EMV) confirmed the importance of this Nethyl carboxamide as this second NH moiety also interacts with Asp73. Similarly to 66 and 67,293 a trifluoromethyl group on the pyrazole component was found ideal for an additional interaction with a hydrophobic pocket, and the carboxylic acid interacts with Arg136. Moreover, the pyridine ring featuring this carboxylic acid group interacts with the Glu50−Arg76 salt bridge.299 Finally, as shown in Figure 20, the superposition of 71 and 72 with the conformations and spatial positions they


tuberculosis indeed lacks a topoisomerase IV, which would have led to very low mutation frequency observed for dual targeting inhibitors. Attempts to cocrystallize thiazolo[5,4-b]pyridine derivatives and the GyrB protein of M. tuberculosis have, so far, failed. On the other hand, its sequence homology with the S. pneumoniae topoisomerase IV ParE protein led to the choice of this domain for cocrystallization studies, which provided two recently disclosed structures of thiazolo[5,4-b]pyridines bound to S. pneumoniae ParE (PDB codes 4MBC and 4MB9). Interestingly, the inhibitor side chains (see Supporting Information), corresponding to the tetrahydrofuran ring of compound 64, appears to lie outside of the ATP-binding pocket in both structures.287 Another approach involved deconstruction of the core bicycle and led to pyridine derivatives such as 66 and 67.288−291 This pyridine ring was demonstrated to be essential, as analogues featuring a benzene ring instead were devoid of effect on E. coli DNA gyrase ATPase activity.292 Another very recent report293 provides an account of the research program that led to 66 and 67 along with X-ray-based structures of these two compounds bound to S. pneumoniae ParE ATPase domain (PDB codes 4LPO and 4LBP). Interestingly, in these structures, an opposite orientation was observed for the 3pyridyl moieties of acid-bearing analogue 66 and oxadiazolone analogue 67. This difference may or may not reflect what takes 2326


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residue, thus illustrating the accommodation capacity of the ATP-binding pocket. The weakly acidic oxadiazolone component of 73 was found to be optimal for its interaction with the Arg136 residue as well as for improving logD and led to strong inhibitors of type IIA topoisomerases with good antibacterial effects.299 The same research group also designed aminopyrimidines such as 74, which has few structural points in common with 72 and 73. In this case, as for the triazines 43− 45, the aminopyrimidine component likely provides the donor−acceptor pair interacting with the Asp73 residue, while the carboxylic acid function reaches for the Arg136 residue (many other acidic group were claimed).150 A recent extensive preclinical study of 72 has reported favorable data, including in vivo efficacy.300 Much more recently, an original series of quinazolinones such as 75 and 76 were disclosed. These S. aureus DNA gyrase inhibitors turned out to display antibacterial properties, including against E. coli.301 Again, when the distance between the proton donor−acceptor pair and the carboxylic acid functions of 75 and 76 is considered, the degree of “leeway” mentioned above is apparent. From the initial pyrazolthiazole derivative 77 found by highthroughput screening, an X-ray-derived structure of this compound in the GHKL subdomain of S. aureus DNA gyrase (PDB code 3G75) was obtained. As depicted in Figure 21, the two pyrazole nitrogens provide the hydrogen donor/acceptor pair interacting with the Asp73 residue; unexpectedly, the resident water molecule is missing from the reported structure.302 The lack of a polar function on the thiophene ring of 77, able to interact with Arg136, probably explains its relatively modest effect on E. coli DNA gyrase (Ki = 2.9 μM). An optimization program led to the ethyl amide 78, which inhibited E. coli DNA gyrase 60 times better (Ki = 0.047 μM) but displayed only a moderate antibacterial effect.302 Replacement of the amide function of 78 by the carbamate seen in the structure of the modest antibacterial 79 also led to DNA gyrase inhibition, although it was found to be a hundredfold stronger on E. coli enzyme (Ki < 0.004 μM) than on the one from S. aureus (Ki = 0.14 μM).302 The X-ray structures of 79 bound to the GHKL subdomain of E. coli DNA gyrase (PDB code 3G7E) pointed out the existence of a larger pocket in the case of E. coli, which could thus better accommodate its carbamate moiety.302 Very recently, a series of amide-bearing derivatives such as 80 were found by high-throughput screening specifically focused on Mycobacterium smegmatis DNA gyrase ATPase activity. As depicted, the structure of 80 bound to the GHKL subdomain of M. smegmatis DNA gyrase (PDB code 4B6C) pointed out that its amide interacts with Asp73 as the carbamate moiety of novobiocin (1), the ether function interacts, via a resident water molecule, with the Arg136 residue, and the phenyl ring linking these two key moieties is able to reach for the Glu50−Arg76 salt bridge.303 Moreover, the rather large lipophilic dimethylphenyl group on the pyrazine ring turned out to fit well in a hydrophobic cavity present in M. smegmatis DNA gyrase ATPbinding site. On the other hand, the very much decreased effect on other bacterial DNA gyrases was explained by the absence of such a large hydrophobic pocket in this area. The even more lipophilic pyrimidine derivative 81 was found to be 30 times more active than 80 on M. smegmatis GyrB and displayed a promising effect on M. tuberculosis growth in vitro. The orienting effect of the secondary amine function of 80 and 81 on their amide moiety by an intramolecular hydrogen bond is actually very much reminiscent of a series of strong HSP90 ATPase inhibitors featuring such a motif.304,305 More recently, a

Figure 20. (Top) Structures of 70−76. (Middle) Zoomed-in view of binding mode for 71 and 72 with GHKL subdomain of S. pneumoniae topoisomerase IV (PDB codes 4EM7 and 4EMV) in the same orientation shown in Figure 14. (Bottom) Superposition of 71 and 72.

adopt in the ATP-binding site of S. pneumoniae ParE points out how much “leeway” there is in the design of such inhibitors. Indeed, quite a shift can be seen for the position of the carboxylic acid key component interacting with the Arg136 2327


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virtual fragment-based search refined by 1H/15N correlation in NMR spectroscopy. From the initial weak hit 82, the addition of a coumarin ring allowed an interaction with Arg136, and the large 4-terbutylbenzyl group was introduced in order to fill the hydrophobic pocket present in this direction. As in other cases, the Arg136 residue could also be reached with a carboxylic group instead of a coumarin and, as depicted, the binding mode of the analogue 84 was confirmed by X-ray crystallography.239 Further researches led to the cyclohexyl ester 85 with a greatly improved antibacterial activity spectrum. This fact could be due in part to better membrane permeability provided by the less rigid cyclohexyl ring.307 Deconstruction of the indazole ring was also undertaken and this approach provided antibacterial pyrazoles such as 86. The analogues with an E configuration were found to be more active than their Z homologues (which readily isomerizes in solution under light).308 Moreover, a patent has claimed amides featuring a combination of the indazole along with a thiazole ring quite reminiscent of the one seen in the pyrazole derivatives 77−79 depicted above. Because of a lack of detailed biological data, out of the many compounds claimed, the depicted amide 87 was randomly chosen.309 Finally, an additional series, resulting from an NMR fragmentbased search, has been disclosed recently. This series also features a 3-pyridylthiazole component and, interestingly, if the methyl derivative 88 is mostly devoid of effect on an array of DNA gyrases, the propyl analogue 89 turned out to be the strongest antibacterial of the series.310

Figure 21. (Top) Structures of 77−81. (Bottom) Zoomed-in views of binding modes for 77 (in blue) with GHKL subdomain of S. aureus DNA gyrase (PDB code 3G75), for 79 (in orange) with GHKL subdomain of E. coli DNA gyrase (PDB code 3G7E), and for 80 (in cyan) with GHKL subdomain of M. smegmatis DNA gyrase (PDB code 4B6C).

series of bisacylhydrazides featuring a pyrazole ring were reported to modestly inhibit DNA gyrase and could have a related binding mode.306 The indazole ring seen in the DNA gyrase ATPase inhibitor 83, depicted in Figure 22, was found by a combination of 2328


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sense.322,323 Ungeremine (92) is also a naturally occurring compound that was reported to be an inhibitor of both bacterial and human topoisomerases.324 Its structure is reminiscent of the benzo[c]phenanthridinium alkaloids that, along with many analogues, have been extensively investigated for their DNA interacting properties, their inhibition of human topoisomerases I and II, and their antitumor potential.325 The charged benzimidazole 93, endowed with quite strong antibacterial properties, was found to weakly inhibit both type IIA topoisomerases.144 The dimeric 4-methoxyphenylbenzimidazole derivative (94) was described for its ability to inhibit bacterial DNA gyrase,326 as were more recent 4-aminated analogues.327 Such derivatives are related to series of neutral or cationic bis-benzimidazoles reported for their antibacterial effects,328,329 including an earlier patent that described a strain of E. coli resistant to 95 featuring a mutated DNA gyrase.330 In any case, this class of compounds has also been extensively studied for their interaction with DNA as well as their inhibition of mammalian topoisomerase I to explain their cytotoxic effect.331−335 Two tetracyclic structures likely to interfere with DNA have also been reported.336 The polyphenolic quercetin and 3-O-glycosylated derivatives were reported to be inhibitors of GyrA337,338 and GyrB.339 However, these results should be reconsidered in light of the occurrence of quercetin aggregates, which make this compound apparently active on far too many biochemical assays.340,341 Despite this, actual docking into DNA gyrase of such compounds has been found plausible,342 and modified 3-O-glycosides, such as 96, were reported more recently for DNA gyrase inhibition as well as antibacterial properties.343 More recently, polyphenolic bisquinones such as diospyrin (97) were reported for their inhibition of bacterial DNA gyrase. This compound was suggested to bind the ATPase domain but not the ATPbinding site.344 Interestingly, diospyrin (97) has also been reported to owe its leishmanicidal effect to the inhibition of topoisomerase I of Leishmania donovani.345 Moreover, an inhibition effect on a mammalian RNA splicing process, in which topoisomerase I is involved, was reported for diospyrin (97) and some analogues.346 In the same vein, the ubiquitous polyphenolic flavonoids were found to also have an effect on DNA gyrase.347,348 From a program aiming at the preparation of pyrazolines featuring relatively reactive substituents,349,350 the acetone adduct 98, depicted in Figure 24 (certainly not the isoquinoline described in the report), stood out for its antibacterial properties, possibly caused by an effect on DNA gyrase.349 Another research program, based on phenotypic screening using a genetically altered E. coli strain devoid of efflux pump, was followed by determination of the actual biochemical target of the hits found. This program yielded gyramide C (99), a representative of a series of N-benzyl-3-sulfonamidopyrrolidines that inhibit E. coli DNA gyrase without any crossresistance with fluoroquinolones. Unfortunately, this series should only be considered as a starting point for a medicinal chemistry program, as they are inactive on efflux pump-efficient Gram-negative bacteria.351,352 Concerning other pyrazole-based inhibitors of DNA gyrase, the derivative ES-0615 (100) was found by whole cell-screening.144 If this compound could conceivably be an inhibitor of the ATPase function of DNA gyrase, a medicinal chemistry program led to far more efficient N-aryl analogues such as ES-1273 (101).353−355 As this N-aryl ring component could not possibly fit in models of the ATPbinding pocket, further work proved that such compounds are

4.4. Several Inhibitors Lacking a Defined Binding Mode to Type IIA Topoisomerases

Simocyclinone D8 (90), depicted in Figure 23, is another naturally occurring inhibitor of DNA gyrase featuring a


coumarin moiety. However, this compound does not affect topoisomerase IV and it turns out to prevent DNA binding, not ATP hydrolysis, when inhibiting DNA gyrase.311,312 Interestingly, an X-ray structures of simocyclinone D8 (90) bound to a E. coli GyrA fragment was reported (PDB code 2Y3P)313 and the same research group found that this compound also has an affinity for the GyrB47 fragment, which does not contain the ATP-binding pocket, thus suggesting dual binding on the whole enzyme.314 In any case, this compound is not selective against bacteria, as it was also reported to inhibit human topoisomerases II315 and I.316 The mammalian topoisomerase II inhibitor clerocidin (91)317 was reported to inhibit DNA gyrase.318 However, structural features such as the epoxide function and the unsaturated aldehyde make this compound the archetype of a frequent hitter which usually displays effects on most if not all biochemical assays. Indeed, this compound was shown to be an alkylating agent319 even prone to react with commonly used buffer320 or adenine.321 Such a result is not specific to naturally occurring compounds as, fairly repeatedly, virtual screening followed by a biochemical assay will deliver “hits” that cannot be exploited in the medicinal chemistry 2329


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the ill-fated Viquidacin/NXL 101 (104).358 The former was cocrystallized (PDB code 2XCR) with a DNA oligonucleotide and the catalytic core (breakage−reunion and TOPRIM domains) of S. aureus DNA gyrase.40 The latter underwent a phase I clinical study in 2008 that, despite favorable preclinical data, had to be discontinued because of the occurrence of QTc prolongation. This forbidding cardiac side effect can be ascribed to inhibition of potassium channels such as the human ether ago-go-related gene (hERG) protein,359,360 although in the preclinical studies of 104, this parameter was not a cause of concern.51 In any case, a hERG inhibition issue was also noted in the course of extensive preclinical studies of 105, a hydroxylated analogue of 103.361 However, these results do not seem to have deterred all the actors in the field as patents and publications, many focusing on the hERG inhibition issue, have kept appearing and fairly promising series are currently being developed. Concerning the actual binding mode of such compounds, as mentioned above, the remarkable X-ray structure of a doublestranded DNA with 103 sitting on the binary rotation axis in the catalytic core was reported (PDB code 2XCR).40 It appears that the quinoline ring (heterocycle A) is intercalated between two bases of the DNA strand, whereas the [1,3]oxathiolo[5,4c]pyridine (heterocycle B) is bound to a hydrophobic pocket made by the interactions of the two breakage−reunion domains while the enzyme adopts a pre-DNA cleavage conformation. Thus, as highlighted in the superposed view pictured in Figure 26, the binding site of 103 is close but not overlapping with the two symmetric quinolone binding sites (PDB code 3RAD). This fact explains the lack of cross-resistances observed between this class of compounds and fluoroquinolones. Interestingly, the driving force in the medicinal chemistry for this class of compound is not only to find bioisosteric replacements for each of the three components depicted in the general structure 102 but also to find new chemistry. As previously noted,52 it is variations, depicted for quinine (106)363−365 in Figure 27, of the age-old transformation of cinchonine into cinchotoxine366,367 that provided, via the antiarrhythmic viquidil, the asymmetric building block 107 used for the series leading to Viquidacin/NXL 101 (104). A well-illustrated account of the iterative process368−370 that led to 104 has been published recently.371 Similarly, from hydroquinidine (108), three chemical steps led to 109, one of the first patented inhibitor of this class.357 Indeed, despite about five generations of research, the chemistry possible on a given structure remains one of the limiting factors in the design of original drugs. In these times of rationalized medicinal chemistry, the recently reported use of zinc sulfinates and tertbutyl hydroperoxide to quickly dress the quinoline ring of hydroquinidine (108) and obtain the previously hard-to-get 110372 is probably the most recent demonstration of this often overlooked fact. It is beyond the scope of this review to describe and comment on all the results described for this class of inhibitors, which have been the subject of close to 100 distinct patents along with fewer reports.361,365,373−382 Since a hERG inhibition issue was a recurrent concern for these series, we have tried to provide an illustration of some of the strategies employed to address this aspect, along with the daunting task of securing good in vivo antibacterial effects. Indeed, if 111, depicted in Figure 28, has a good antibacterial profile, it is also a significant inhibitor of the hERG channel in the whole-cell patch-clamp model.383 On the other hand, the deaza analogue 112 is a far


indeed inhibiting bacterial DNA gyrase and topoisomerase IV by another, unidentified mechanism. Moreover, compound 101 was also found to be active on human topoisomerase IIα but not on topoisomerase I.356 4.5. Inhibitors Binding the Catalytic Core of Type IIA Topoisomerases

In 1999, a new type of dual inhibitors of DNA gyrase and topoisomerase IV was disclosed.357 This discovery was even more interesting as the relative ratio of inhibition power for these two enzymes was often opposite to the one usually observed for fluoroquinolones,358 and antibacterial effects were seen even against fluoroquinolone-resistant strains.40,358 As depicted in Figure 25, the “generic” structure 102 of this class of inhibitors is made of two heterocycles connected by a central part, an aliphatic “linker” usually containing basic nitrogen, which is often an aminopiperidine. The two most known compounds of this family are so far GSK-299423 (103)40 and

Figure 25. Structures of 102−105. 2330


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Figure 26. (Top) Front and top views of the catalytic core (color code as in Figure 2) of S. aureus DNA gyrase in complex with 103 (in green CPK format) and DNA (in orange) (PDB code 2XCR). (Bottom) Zoomed-in view of compared interaction mode of 103 (PDB code 2XCR) and the clinafloxacin quinolone362 (PDB code 3RAD) (in yellow stick format). DNA from the quinolone complex structure is shown in yellow.

antibacterial spectrum of amides 113−116. Moreover, as for the pair 111 and 112, a slight drop of antibacterial effect was also seen for the deaza analogues 114 and 116 in comparison with their nitrogen-containing analogues 113 and 115. However, no mention is made in these reports of an eventual hERG inhibition for these analogues.373,374 Aside from this tetrahydro-2H-indazole, pyridine,385 tetrahydronaphthalene,386 dihydrooxazol-2-one,387 triazole,388 trans-decahydroisoquinoline,389 and cyclohexane390 ring systems were also used to replace the aminopiperidine linker or the great many related aminated cycloalkyl systems described in about 50 patents. A third research group reported the optimized analogue 117 or the aza derivative 118 with IC50 values in the patch-clamp Ion Works hERG model391 of 19 and 31 μM, respectively.377 The same research team found that the cyano derivative 119, out of a series of aminopiperidines featuring benzoxazinone for the A ring, was optimum in balancing hERG inhibition (IC50 > 44 μM in the Ion Works assay) and antibacterial activity.375 Further chemistry led to the optically active fluoro derivative

less efficient antibacterial, but close to a 10-fold decrease, from 25 to 200 μM, in hERG inhibition is seen.376 Other approaches led to 105 depicted above, which has a strong in vivo efficacy and promising pharmacokinetic properties although hERG inhibition is seen in the whole-cell patch-clamp model (IC50 = 5 μM).361 In an attempt to avoid the basic aminopiperidine, a possible cause for the effect on hERG,384 tetrahydro-2Hindazole was used as a linker by a second research group, as seen in the structures of the optimized inhibitors 113−116. These compounds displayed strong antibacterial effects on both susceptible and multidrug-resistant Gram-positive strains, as well as on some Gram-negative organisms.373,374 Interestingly, it appears that a basic nitrogen is not necessary as, when comparable, amides in this series are usually more active on the DNA gyrase than the corresponding amines. However, an opposite effect was sometimes noted with inhibition of topoisomerase IV as well as antibacterial activity. In comparison with unsubstituted amides, introduction of a lipophilic chlorine or bromine atom on the benzothiazinone ring improved the 2331


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the Ion Works model) while retaining good in vivo antibacterial properties as well as promising pharmacokinetics and an improved QT profile. Accordingly, this compound, which is efficacious at a dose of 60 mg/kg in a mouse model of infection, has been selected for eventual phase I clinical trials.378 Another actor in the domain has reconsidered the structure of NXL101 (104) and prepared selenium analogues such as the Rdiastereoisomer 121 or the corresponding S-derivative 122. The latter displayed a lowered effect on hERG, as measured by the patch-clamp model, in comparison with the former (IC50 = 12 and 38 μM, respectively).365 A recent report is describing a series of cyclobutyl-bearing analogues such as 123, which turned out to only weakly inhibit S. aureus topoisomerase IV in comparison with its DNA gyrase. Unfortunately, as measured on the patch-clamp model, all the analogues reported so far have unacceptable levels of effect on the hERG channel.380 Tricyclic analogues such as the imidazo[1,2,3-ij][1,8]naphthyridine derivative 124, depicted in Figure 29, were studied for their antimycobacterial properties.392−396 Moreover, the elaborated pyrrolo[3,2,1-de][1,5]naphthyridine GSK966587 (125) was the subject of a synthesis study leading to a much improved route that could provide a manufacturingscale process to prepare this inhibitor.397 Extensive preclinical data have also been reported recently for 125.381 In vivo efficacy in a S. pneumoniae mouse respiratory tract infection model was seen, as well as a very low effect on the hERG channel (IC50 = 239 μM on patchXpress model). Its progression to clinical trials was, however, stopped as hepatic portal tract lesions were observed in a dog safety toxicology study. Since this side effect was not found to be inherent to this class of inhibitors, it did not prevent further work on identifying better-suited inhibitors.381 Also of note in this report is the Xray structure obtained of 125 bound to the catalytic core of S. aureus DNA gyrase also containing a DNA oligonucleotide (PDB code 4BUL). Interestingly, the DNA strand used to obtained crystals with 103 did not a give stable complex in the case of 125, and a search for another optimal strand had to be conducted.381 This fact has probable repercussions for any in vitro structure−activity relationships for this class, as the inhibition measured could apparently depend on the DNA sequence used in the in vitro assay. It could thus be of interest to mirror the previous extensive study of the DNA sequence determining the localization of strand breaks caused by various fluoroquinolones398 with this class of inhibitors. The specific antimycobacterial effect for these tricyclic analogues was also reviewed and an efficacy was demonstrated in an acute mouse model of infection for 126. However, the inhibition of hERG by 126 also turned out to be an issue.253 Finally, with a low effect on the hERG channel (IC50 = 1400 μM in the patchclamp electrophysiology model), the recently disclosed analogue GSK2140944 (127) is currently undergoing phase I clinical trials.399,400 Extensive biological results of the use of 3aminotetrahydropyran401,402 as a replacement of the aminopiperidine linker were reported recently.382 This work led to dual inhibitors of DNA gyrase and topoisomerase IV such as 128 (respective IC50 of 0.03 μM and 0.03 μM on gyrase and topoisomerase IV of S. aureus) and 129 (respective IC50 of 0.03 μM and 0.125 μM on gyrase and topoisomerase IV of S. aureus). The former inhibitor is a broad antibacterial but also blocks the hERG potassium channel (54% block at 10 μM). On the other hand, its analogue 129, differing only in the nature of heterocycle B, has a lower effect on hERG (19% block at 10 μM). Compound 129 has also favorable preclinical pharmaco-



120, which retained a cyano moiety on the A ring. Introduction of the electron-attracting fluorine group on the piperidine ring of 120 greatly lowered the effect on hERG (IC50 = 233 μM in 2332


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of the current competition in the domain as well as tributes to medicinal chemists’ ingenuity. As a concluding part of this section, it is fit to mention a high-throughput screening, based on a set of antibacterial assays, that delivered the remarkable barbituric derivative PNU286607/QPT1 (134), depicted in Figure 30. From this quite


simple phenotypic approach, further studies demonstrated that this initial hit is actually orally active in vivo in a systemic mouse infection model (ED50 = 19.5 mg/kg) and that it is an inhibitor of bacterial DNA gyrase. Interestingly, neither crossresistance with fluoroquinolones nor any effect on human topoisomerase II was observed.411−413 More recent work on this series led to the antibacterials 135 and 136, featuring either an additional pyrazine ring,414 an ethynylpyridine as in 137,415 a pyrazole as in 138,416 or an adjacent isoxazole ring as seen for compounds such as 139−141.136,417 The antibacterial spectra of this last series pointed out in vitro effects against Grampositive and fastidious Gram-negative bacteria and atypical and anaerobic bacterial isolates,418 as well as, for AZD0914 (141), all the tested wild or resistant strains of Neisseria gonorrheae.419 Moreover, an in vivo efficacy was also demonstrated in a mouse thigh model of S. aureus infection for this series.420 Further work should be necessary to elucidate the actual binding mode of such inhibitors, although the fairly unprecedented Asp437 to Asn or Val point mutation on the S. aureus GyrB gene (corresponding to Asp426 in E. coli GyrB) is associated with resistance to 134.412 More recent studies of the mutations associated with S. aureus resistance to benzisoxazole analogues 139−141 led to finding three alterations of the GyrB gene:


kinetics parameters and demonstrated in vivo efficacy on a S. aureus neutropenic murine thigh model of infection at the dose of 40 mg/kg. Moreover, the spontaneous resistance development frequencies in S. aureus were determined for 128 and 129 in comparison with the reference inhibitor 104, which inhibits DNA gyrase only (respective IC50 of 0.125 μM and 128 μM on gyrase and topoisomerase IV of S. aureus). This report thus provided another demonstration that dual inhibitors of DNA gyrase and topoisomerase IV are leading to less spontaneous resistance development in bacteria. In the present case, 128 and 129 led to between 10- and 100-fold less resistance in S. aureus than the reference DNA gyrase inhibitor 104.382 A different point of attachment was recently found to be possible for heterocycle A, as seen for the 2-quinoxalinyl ether 130.403 Finally, tricyclic analogues 404 such as 131,405 oxazolinones406,407 such as 132,408 or the quite altered spiro derivatives409 such as 133410 are probably good illustrations 2333


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well that enzymes with a “GHKL-folded” ATPase domain are structurally quite different when it comes to binding inhibitors (if an aspartic residue equivalent to Asp73 is seen in the ATPbinding pocket of HSP90, the Arg136 is a histidine and no Glu50−Arg76 salt bridge is present). In any case, the current knowledge on type IIA topoisomerases or HSP90434,435 has come from X-ray structures of ATPase inhibitors bound to these enzymes. The future will see if (and how) inhibitors of the ATPase domain site of human or viral topoisomerase II can be found.

Asp437Val, also mentioned above; Ser442Pro; and Pro456Leu.421 Further studies focusing on 141 and N. gonorrheae pointed out mutations on the C-terminus of GyrB (Asp429Asn or Lys450Thr).422 Interestingly, at least two of the mutations observed for S. aureus are neighbors to the mutation hot spot seen in the quinolone resistance determining region (QRDR) leading to fluoroquinolone resistances423,424 or the mutations seen for resistance against 105.358 Accordingly, these results strongly hint that a third kind of binding of small molecules to the catalytic core of type IIA topoisomerases is possible. Finally, and of much interest, phase I clinical trials of 141 have been initiated.425

ASSOCIATED CONTENT 5. CONCLUSION From the discovery that novobiocin (1) and fluoroquinolone antibiotics were selectively acting on bacterial type IIA topoisomerases, a remarkable number of series of inhibitors of these enzymes has been reported. The design of biochemical or cellular assays, amenable to high-throughput screenings, along with X-ray-derived structures of the early inhibitors bound to DNA gyrase, were instrumental in this. From these structures, an array of strategies, which are today called fragment-based approaches, provided quite a number of additional starting points for medicinal chemists. The difficult task of transforming good type IIA topoisomerase inhibitors into actual antibacterials provided a lot of insights into the delicate balance required between their lipophilicity and water solubility. Reviews concerning this aspect describe what parameters can help in the design of compounds prone to passive diffusion through the bacterial porin channels as well as the lipidic membrane bilayers.426,427 Moreover, efflux pumps, especially in Gram-negative bacteria, have to be taken into account in such designs, thus leading to inhibitors in equilibrium between a neutral and a protonated form.428,429 Following the avoidance of these pitfalls, an impressive list of additional requirements exists before any compounds can reach the stage of clinical trials. A recent study on the early assessment of antibiotic off-target effects on bacteria pointed out that in a given series, compounds 49−52 in this case, relatively benign structural changes can indeed lead to nonspecific antibacterial effects.58 The coming years will see whether some of the inhibitors described here will reach and pass these stages. In any case, as for any other diseases involving infectious vectors, the proper management,430 including avoiding antibiotic misuse or overuse,431−433 of a new arsenal of non-cross-resistant drugs will be a crucial strategy to stem the unavoidable emergence of multiresistant infections in the future. Today, possibly along with 120,378 the aminopiperidine 127399 and 141425 are the only non-quinolone inhibitors of bacterial type IIA topoisomerases undergoing phase I clinical trials. Accordingly, it is probably essential to design additional original chemical entities to inhibit these enzymes, with a potential for their adaptation to human pharmacology. The extensive work done on inhibition of HSP90,434,435 another enzyme featuring a GHKL subdomain with a similar ATPbinding site, could be a different starting point in this regard. Interestingly, aside from novobiocin (1), which turns out to inhibit HSP90 by another binding mode,184 none of the ATPase inhibitors of the bacterial type IIA topoisomerases appears to inhibit HSP90 and, as far as we could tell, vice versa. Moreover, inhibitors binding (selectively or not) the ATPbinding site of human topoisomerase II, which also features a GHKL fold, have yet to be reported. These facts illustrate quite

S Supporting Information *

Sequence alignment for GyrB or ParE ATPase domains of many species; a table listing all the X-ray structures reported with depictions of the corresponding ATPase inhibitor bound; and larger versions of Figures 2, 3, 5, 6, 9, 11, 14−18, 20, 22, and 26. This information is available free of charge via the Internet at http://pubs.acs.org/.

AUTHOR INFORMATION Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest. Biographies

Claudine Mayer was born in 1969 in Strasbourg, France. She initially studied chemistry at the European High Industrial Chemistry School (EHICS) and obtained a Ph.D. in structural biology and crystallography in 1997 from the Louis Pasteur University, Strasbourg, under the supervision of Dr. Dino Moras. She spent then three postdoctoral years in the Biological Structures and Biocomputing Programme at the EMBL, Heidelberg, Germany, in the Dr. Dietrich Suck’s unit. She was then associate professor from 2000 to 2008 at the Pierre et Marie Curie University, Paris 6, in the Mineralogy and Crystallography Laboratory, focusing her research on structural studies of proteins implicated in the biosynthesis of peptidoglycan. Since 2008, she has been a professor at Paris Diderot University and joined the Structural Microbiology unit headed by Dr. Pedro Alzari at the Institut Pasteur. She has 20 years of expertise in solving DNA and protein structures by X-ray diffraction and has been working now, for over 6 years, on Mycobacterium tuberculosis DNA gyrase. 2334


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Yves L. Janin was born in 1965 in Paris, France. He studied chemistry initially at Bordeaux I and , then the Ecole Nationale Supérieure de Chimie de Paris and obtained a Ph.D. in organic chemistry in 1993, from the Pierre et Marie Curie University, Paris 6, under the guidance of Dr. Emile Bisagni at the Institut Curie. Following a year without any employment in science, he joined, for a two-year postdoc, Dr. David S. Grierson at the ICSN, Gif/Yvette, France. He then enjoyed a postdoctoral year in Professor Povl Krogsgaard-Larsen’s research laboratory at the Danish School of Pharmacy in Copenhagen. Following six years in the Institut Curie as a junior CNRS scientist, he went on a sabbatical year in Vitry/Seine Aventis research facilities before joining the Institut Pasteur in 2004. Throughout 23 years he has worked on various medicinal chemistry-driven designs and syntheses of heterocyclic derivatives concerning oncology, virology, neurobiology, and currently infectious diseases.

ACKNOWLEDGMENTS Professor D. B. Wigley is acknowledged for kindly providing us with a few PDB structures not currently available in the Brookhaven database. Dr. Emile Bisagni is acknowledged for support and interest. Dr. Eric Bacqué, Michel Tabart, and Neil D. Pearson, as well as the anonymous referees, are also acknowledged for improving the accuracy of this review with their comments and suggestions. This work was supported by the Institut Pasteur (PTR Grant 367). REFERENCES (1) Champoux, J. J. Annu. Rev. Biochem. 2001, 70, 369. (2) Corbett, K. D.; Berger, J. M. Annu. Rev. Biophys. Biomol. Struct. 2004, 33, 95. (3) Forterre, P.; Gribaldo, S.; Gadelle, D.; Serre, M. C. Biochimie 2007, 89, 427. (4) Kampranis, S. C.; Maxwell, A. Proc. Natl. Acad. Sci. U.S.A. 1996, 93, 14416. (5) Strahilevitz, J.; Hooper, D. C. Antimicrob. Agents Chemother. 2005, 49, 1949. (6) Silver, L. Nat. Rev. Drug Discovery 2007, 6, 41. (7) Gellert, M.; Mizuuchi, K.; O’Dea, M. H.; Nash, H. A. Proc. Natl. Acad. Sci. U.S.A. 1976, 73, 3872. (8) Gellert, M.; O’Dea, M. H.; Itoh, C.; Tomizawa, J. Proc. Natl. Acad. Sci. U.S.A. 1976, 73, 4474. (9) Ryan, M. J. Biochemistry 1976, 15, 3769. (10) Barton, N.; Crowther, A. F.; Hepworth, W.; Richardson, D. N.; Driver, G. W. British Patent BR 830832, 1960. (11) Sugino, A.; Peebles, C. L.; Kreuzer, K. N.; Cozzarelli, N. R. Proc. Natl. Acad. Sci. U.S.A. 1977, 74, 4767. (12) Cheng, G.; Hao, H.; Dai, M.; Liu, Z.; Yuan, Z. Eur. J. Med. Chem. 2013, 66, 555. (13) Goss, W. A.; Deitz, W. H.; Cook, T. M. J. Bacteriol. 1965, 89, 1068. 2335


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