Perspective Cite This: J. Med. Chem. XXXX, XXX, XXX−XXX
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Battle against Vancomycin-Resistant Bacteria: Recent Developments in Chemical Strategies Geetika Dhanda, Paramita Sarkar, Sandip Samaddar, and Jayanta Haldar*
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Antimicrobial Research Laboratory, New Chemistry Unit, Jawaharlal Nehru Centre for Advanced Scientific Research, Jakkur, Bengaluru 560064, Karnataka, India ABSTRACT: Vancomycin, a natural glycopeptide antibiotic, was used as the antibiotic of last resort for the treatment of multidrug-resistant Gram-positive bacterial infections. However, almost 30 years after its use, resistance to vancomycin was first reported in 1986 in France. This became a major health concern, and alternative treatment strategies were urgently needed. New classes of molecules, including semisynthetic antibacterial compounds and newer generations of the previously used antibiotics, were developed. Semisynthetic derivatives of vancomycin with enhanced binding affinity, membrane disruption ability, and lipid binding properties have exhibited promising results against both Gram-positive and Gram-negative bacteria. Various successful approaches developed to overcome the acquired resistance in Gram-positive bacteria, intrinsic resistance in Gram-negative bacteria, and other forms of noninherited resistance to vancomycin have been discussed in this Perspective.
1. INTRODUCTION The emergence and spread of antimicrobial resistance (AMR) globally poses a major threat to the management of infectious diseases, resulting in high morbidity and mortality.1 The World Health Organization’s (WHO) Global Antimicrobial Surveillance System (GLASS) revealed high levels of resistance in a number of serious bacterial infections worldwide. Resistance in bacteria such as Escherichia coli, Klebsiella pneumoniae, Staphylococcus aureus, and Streptococcus pneumoniae, followed by Salmonella spp. are among the most commonly reported.2 To tackle the rapid emergence of antimicrobial resistance, initiatives were taken by various health organizations and governments, which resulted in the approval of several new antibiotics. Five new classes of antibiotics, lipopeptides (daptomycin), oxazolidinones (linezolid), pleuromutilin (retapamulin), macrocyclic antibiotics (fidaxomicin), and diarylquinoline (bedaquiline), were introduced into the market. The other new antibiotics, which were modifications of the previously existing antibiotics, had limited usefulness due to the pan-class mechanisms of resistance in bacteria. This lack of novel scaffolds from targetbased or phenotypic-screening methods had resulted in the withdrawal of pharmaceutical companies from antibiotic research.3 This further aggravated the problem of AMR. Another aspect of bacterial infection that had been given little attention to earlier is the phenomenon of “noninherited” resistance to antibiotics. In this case, bacteria that are inherently susceptible to antibiotics are often phenotypically resistant to them.4 The ability of bacteria to cause intracellular infections, form biofilms, and go into a metabolically inactive state contributes to this phenotypic “noninherited” resistance. This noninherited © XXXX American Chemical Society
resistance causes an additional burden to AMR and makes treatment more challenging. Among all the classes of approved antibiotics, the glycopeptide antibiotics had the highest longevity in the clinic. The advantage of this class of antibiotics was that they worked by binding to the substrate for peptidoglycan synthesis instead of an enzyme, which is prone to mutations, thereby leading to a decreased propensity of resistance. Vancomycin was reserved as an antibiotic of last resort for the treatment of complicated infections caused by multidrug-resistant Gram-positive bacteria which prevented the widespread development of resistance to it. It was not until almost three decades from vancomycin’s introduction in the clinic that resistance to it was observed. The emergence of resistance to this antibiotic raised alarms in the clinic and in the scientific community, calling for immediate measures to curb resistance. According to the list of priority pathogens published by WHO in 2017, vancomycin-resistant Enterococcus faecium and vancomycin-intermediate and resistant S. aureus (VISA and VRSA) come under the high priority category because the number of options for the treatment of vancomycin-resistant bacteria still remain limited.5 This perspective provides an overview of the current treatment options for vancomycin-resistant bacterial infections. Various approaches that have been developed to overcome acquired and noninherited resistance to vancomycin in bacteria have also been highlighted. Additionally, the strategies to increase the spectrum of activity of vancomycin against Gramnegative bacteria have been discussed. Received: July 11, 2018 Published: November 7, 2018 A
DOI: 10.1021/acs.jmedchem.8b01093 J. Med. Chem. XXXX, XXX, XXX−XXX
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Figure 1. Glycopeptide progenitors.
Figure 2. Mechanism of action of vancomycin.
2. GLYCOPEPTIDE PROGENITORS
ristocetin A, teicoplanin, and complestatin are some molecules belonging to these subclasses, respectively.6 Vancomycin (Figure 1) is the first molecule from this class of antibiotics, which was isolated by Eli Lilly in 1953 and introduced in clinic in 1958.7 Teicoplanin is another clinically relevant molecule which was first reported in 1978 and approved for clinical use in 1988 in Europe.8 Vancomycin contains five aromatic amino acids and two aliphatic amino acids, thus belonging to subclass I of
Glycopeptide antibiotics constitute an important class of cellwall biosynthesis inhibitors. They are glycosylated heptapeptides produced by a group of soil actinomycetes and are composed of a tricyclic or tetracyclic nonribosomal peptide core. The glycopeptides are categorized into five different structural subclasses, I−V, based on the amino acid residues for amino acids 1 and 3 in the heptapeptide. Vancomycin, actinoidin A, B
DOI: 10.1021/acs.jmedchem.8b01093 J. Med. Chem. XXXX, XXX, XXX−XXX
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Figure 3. Acquired resistance to vancomycin; VSSA = vancomycin-susceptible S. aureus, VISA = vancomycin intermediate S. aureus, hVISA = heterovancomycin intermediate S. aureus, VRSA = vancomycin-resistant S. aureus, VRE = vancomycin-resistant Enterococci.
makes the glycopeptide antibiotics less susceptible to resistance as compared to the enzyme-targeting antibiotics, which are easily rendered ineffective due to genetic alterations. It was due to this unique mechanism of action that vancomycin enjoyed decades of resistance-free use.
glycopeptide antibiotics. Teicoplanin (Figure 1) contains seven aromatic amino acids and a long fatty acid chain linked to the glucosamine sugar, thus being a lipoglycopeptide. Clinically employed teicoplanin is a mixture consisting of teicoplanin A2-1 to A2-5, with A2-2 being the major component. These drugs, especially vancomycin, are mainstays in the treatment of lifethreatening infections due to methicillin resistant S. aureus (MRSA).8 Vancomycin has been recommended intravenously as a treatment for complicated skin structure infections, endocarditis, and bloodstream infections caused by MRSA. Despite the advantages of vancomycin, there were initially many side effects associated with its intravenous administration, including nephrotoxicity, red-man syndrome, and ototoxicity, which have now been resolved due to better purification techniques. It was associated with relatively poor pharmacokinetic (half-life = 4−11 h) and tissue penetrating properties as compared to other glycopeptide antibiotics. Sometimes, teicoplanin is preferred over vancomycin due to its better potency against various clinical isolates belonging to Enterococcus, Staphylococcus, and Streptococcus genera and its better tolerability.8,9 It has better pharmacokinetic properties (half-life = 30 h) and may be administered intravenously or intramuscularly.
4. RESISTANCE DEVELOPMENT The first instance of vancomycin resistance occurred in Enterococcus faecium in France in 1986.11 In the USA, the rise of vancomycin-resistant Enterococci (VRE), a prolific colonizer, gained pace due to the ever-increasing use of vancomycin in hospital settings. In Europe, it happened in communities, probably due to overuse of avoparcin (another glycopeptide antibiotic, used as a growth promoter in livestock).12 Later, in 1996, S. aureus with decreased susceptibility to vancomycin was first isolated from an infant patient admitted in a hospital in Japan.13 This vancomycin intermediate S. aureus (VISA) strain (Mu50) has been serving as a typical VISA strain with vancomycin minimum inhibitory concentration (MIC) of 8 μg mL−1 since isolation. The first report of high vancomycin resistance in S. aureus, which is known as vancomycin resistant S. aureus (VRSA), came in 2002 as a clinical isolate with MIC > 32 μg mL−1 accompanied by VRE (vanA positive, vancomycin resistance gene cluster), which was identified from a catheter-related infection of a hospitalized patient in USA.14 A strain of S. aureus is considered to be a hetero-VISA (hVISA) strain if it contains subpopulations of cells that grow on the 32 μg mL−1 VRE-VanB (2 μg mL−1) VRE-VanA (36 μM)
62 62
62 65
VRE-VanA (0.7 μM)
65
VRE-VanA (11 μM)
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•[Ψ[C(S)NH]Tpg4] vancomycin •CBP derivative of [Ψ[C(S)NH]Tpg4] vancomycin (2c) •cyclic and acyclic sugars conjugated with the C-terminus of vancomycin, e.g., lactobionic acid−vancomycin conjugate (3) •lipophilic lactobionic acid−vancomycin conjugate for membrane-anchoring properties, e.g., lactobionic acid−vancomycin conjugate with decyl moiety at the vancosamine (4) •Bis (vancomycin) carboxamides (5a−5c)
•vancomycin aglycon dimer containing two permanent positive charges in the linker (10) •lipophilic vancomycin aglycon dimer with an octyl chain (for membrane-anchoring properties) (11) •vancomycin homodimers and heterodimers by linking azidefunctionalized C-terminus vancomycin derivatives with alkyne-functionalized C-terminus vancomycin derivatives (12a−12c)
67 VRE-VanB (2 μg mL−1) VRE (1−2 μg mL−1) VISA (1 μg mL−1) VRE-VanA (0.8 μg mL−1) VRE-VanB (0.28 μg mL−1) VRE-VanC (0.03 μg mL−1) VRE-VanA (48 μM) VISA (0.1 μM) VRE-VanA (2.5 μM) VISA (0.6 μM) VRE-VanB (0.8 μg mL−1)
68 69 73
74 74 75
VRE-VanB (1.6 μg mL−1)
76
VRE-VanB (2 μg mL−1)
77
78
•attachment of lipophilic quaternary ammonium groups with alkyl chains (octyl and tetradecyl-best derivatives) (17a, 17b)
VRE-VanB (0.25−1 μg mL−1) VRE-VanS (0.25−0.5 μg mL−1) VRE-VanA (16 μg mL−1) VRE-VanA (1−2 μg mL−1) VRE-VanB (≤0.06 μg mL−1) VISA (0.12 μg mL−1) VRE-VanA (0.7 μM) VISA (0.36 μM)
•lipophilic vancomycin−sugar conjugates (membrane-disruptive properties and enhanced binding affinity) (17c) attachment of CBP group and peripheral quaternary ammonium salt to [Ψ[CH2NH]Tpg4] (18)
VRE-VanA (0.09 μM) VISA (0.10 μM) VRE-VanA (0.01−0.005 μg mL−1)
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conjugation of vancomycin with moieties consisting of electrostatic effector peptide sequence (EEPS) and a hydrophobic membrane-insertive element (MIE) (19a−19d)
VRE-VanA (0.125 μg mL−1) VRSA (0.05 μg mL−1) VISA (0.03 μg mL−1)
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→targeting the pyrophosphate of the C55−lipid (bactoprenol)
conjugation of dipicolyl-1,6-hexadiamine (Dipi) to the Cterminus of vancomycin (20)
VRE-VanB (1.5 μM) VISA (1 μM) VRE-VanA (2 μM)
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→targeting saccharides of the cell wall
tethering benzoxaborole group to vancomycin (21)
VISA (1−2 μM)
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→lipidation
•methyl ether derivatives of vancomycin aglycon by completely or partially methylating the aryl hydroxyl groups, e.g., tetramethyl ether analogue of vancomycin aglycon, also esterified at the C-terminus (13) •replacement of chloro groups of vancomycin with carbon substituents using Suzuki−Miyaura cross-coupling, e.g., vancomycin derivative by replacement of chloro group of residue-2 with styryl group (14) •positional isomers of lipidated/acylated vancomycin at hydroxyl groups prepared using π (methyl) histidine (Pmh)-based catalysts (15) •lipophilic vancomycin−sugar conjugates with lipophilic substitutions at the vancosamine and sugar moieties on the phenyl ring of the seventh amino acid (16)
→conjugation of lipophilic moieties with a permanent positive charge
→modifications in the [Ψ[CH2NH]Tpg4 vancomycin to confer multiple synergistic mechanisms of action →vancomycin−peptide conjugates
(C) conjugation of groups to enhance interactions with other components of the bacterial membrane and cell wall
refs −1
VRE-VanA (31 μg mL )
•trivalent vancomycin derivatives using amide coupling at Cterminus (6) •multivalent vancomycin derivatives using ROMP (7) •dimers by bridging the saccharide domains of vancomycin in a back-to-back fashion using disulfide and olefin tether (8) •[Pt(en)2(vancomycin)2]2+ (to impart structural rigidity and minimize loss in conformational entropy) (9)
(B) incorporation of membranedisruptive properties
activity (MIC)
•[Ψ[CH2NH]Tpg ] vancomycin 4
F
79
81,82
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DOI: 10.1021/acs.jmedchem.8b01093 J. Med. Chem. XXXX, XXX, XXX−XXX
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Figure 6. Enhancement of binding affinity through core modifications.
6. CLINICALLY APPROVED SEMISYNTHETIC GLYCOPEPTIDES The next generation glycopeptides are semisynthetic derivatives of the naturally occurring glycopeptides, which show enhanced antibacterial activity against vancomycin-sensitive as well as vancomycin-resistant strains. Telavancin (Vibativ), dalbavancin (Dalvance), and oritavancin (Orbactiv) are the clinically approved semisynthetic glycopeptides (Figure 5). These are lipoglycopeptides which have lipophilic moieties linked to the core structure, just like teicoplanin. The long lipophilic moieties help with membrane-anchoring, which enhances binding affinity to the substrate, thus making them more potent than the naturally occurring glycopeptides. By virtue of their lipophilic character, they demonstrate better pharmacodynamic and pharmacokinetic properties.7,8,51 Telavancin consists of a (phosphomethyl) aminomethyl moiety substituted at the para position of the aromatic ring of the dihydroxyphenylglycine residue, to increase solubility and a decylaminoethyl moiety conjugated to the vancosamine sugar of vancomycin to impart membrane-anchoring function. It has enhanced bactericidal properties due to its membrane-disruptive mechanism of action and improved tissue distribution due to the (phosphomethyl) aminomethyl moiety with a terminal half-life of about 8 h.52,53 In 2009, it was approved by the FDA for the treatment of cSSSi and, later, in 2013, for treatment of hospital-acquired and ventilatorassociated pneumonia caused by S. aureus. Dalbavancin is a semisynthetic variant of the teicoplanin family member, A40926. It has a terminally branched dodecyl chain, linked via an amide bond to the glucosamine of the parent drug. This mimics the fatty acyl moiety of teicoplanin which is important to impart membrane anchoring properties. It is also modified through the amidation of the C-terminus carboxyl with an N,N-dimethylpropylamine group. It shows an MIC of 0.1 μg mL−1 against VRE (VanB phenotype).54 Dalbavancin was approved by the FDA in 2014 for the treatment of acute skin and skin-structure infections caused by MSSA and MRSA, vancomycin susceptible E. faecalis, and Streptococci. Its half-life ranges from 149 to 250 h.51 Oritavancin is the N-aryl derivative of the natural product chloroeromomycin. Here, the chlorophenyl-benzyl group is attached to the parent glycopeptide by imine bond formation and subsequent reduction between the corresponding aldehyde
and epivancosamine of chloroeremomycin. The chlorophenylbenzyl group serves to be a good replacement for the fatty acyl groups present in the natural glycopeptides and confers good activity against VRE. In addition to the D-Ala−D-Ala terminus, oritavancin binds to the pentaglycyl bridging segment of the peptidoglycan of Enterococci, thus significantly inhibiting transpeptidation. Oritavancin exhibits MICs of 10-fold more potent than the CBP derivative alone, >1000-fold more potent than the [Ψ[CH2NH]Tpg4] vancomycin pocket analogue, and a striking >10000-fold more potent than vancomycin itself. Recently, in another design, vancapticins were developed by Blaskovich et al. wherein vancomycin was conjugated with moieties that
incorporate membrane-disruptive properties. The membraneinteractive moiety consisted of an electrostatic effector peptide sequence (EEPS) and a hydrophobic membrane-insertive element (MIE) (19, Figure 10).84 The details of the various derivatives which exhibited activity against vancomycin-resistant strains using this strategy have been covered in Table 1, Figure 9, and Figure 10. 7.1.3. Conjugation of Groups to Enhance Interactions with Other Components of the Bacterial Membrane and Cell Wall. Various other components of the bacterial cell membrane can be targeted to inhibit the process of cell-wall biosynthesis. The phosphate group of the C55-lipid (bactoprenol) in the bacterial membrane helps in the transport of the precursor NK
DOI: 10.1021/acs.jmedchem.8b01093 J. Med. Chem. XXXX, XXX, XXX−XXX
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Figure 10. Incorporation of membrane-disruptive properties.
Figure 11. (A) Structure of Dipi-van. (B) Complex formation of Dipi-van-Zn2+ with geranyl pyrophosphate which was identified through mass spectrometry. (C) Identification of intracellular UDPMurNAc-pp in the presence of Dipi-van by monitoring absorbance at λ = 260 nm. Parts B and C reproduced with permission from ref 85. Copyright 2016 John Wiley and Sons.
acetylglucosamine-N-acetylmuramic acid pentapeptide (GlcNAc-MurNAc pp) from the cytoplasm to the exterior of
the cell membrane to further the formation of the peptidoglycan chain. Because the target for vancomycin lies in the vicinity of L
DOI: 10.1021/acs.jmedchem.8b01093 J. Med. Chem. XXXX, XXX, XXX−XXX
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Figure 12. Conjugation of groups to enhance interactions with cell-wall components (21) and vancomycin−nisin hybrid for multiple-target binding (22).
to the amine of vancosamine and N-terminus of vancomycin.86 The rationale behind this was that the benzoxaborole group would form additional interactions with the 1,2- and 1,3-diols of saccharides coating the cell surface and therefore enhance the efficacy of the drugs (21, Figure 12). 7.2. Glycopeptide Hybrids with Other Antibacterials. Antibiotic hybrids provide an interesting approach toward tackling resistance development as they combine the mechanisms of action of different antibiotics. Such hybrids could delay resistance development as genetic alterations in two biological targets are less feasible. In one report, vancomycin−nisin conjugates were developed by linking the C-terminus or Nterminus of vancomycin to the C-terminus of nisin through variable linkers using click chemistry. Nisin is an antimicrobial peptide whose N-terminus is known to bind to the pyrophosphate of lipid II. It was conjectured that through the combination of both moieties in a single molecule, simultaneous lipid II binding of the two parts could lead to increased affinity through bivalency or chelate effect and reinstate the activity of vancomycin to the resistant strains. One of the developed conjugates showed a 40-fold increase in activity against VRE (22, Figure 12).87 Similarly, it was speculated that conjugating a glycopeptide with a β-lactam would result in enhanced antibacterial activity due to the combined mode of action of β-lactams and glycopeptides for cell wall biosynthesis inhibition. With this concept, Theravance Biopharma, Inc., developed vancomycin−cephalosporin hybrids. Out of these, TD-1607 is currently in phase II clinical trials.88,89 Another such hybrid, Cefilavancin (TD-1792) was reported to enter phase III clinical
the membrane, conjugating moieties that can bind to the other components of the membrane is an interesting strategy to enhance activity. In an effort to restore the activity of vancomycin in resistant strains, a Zn2+ binding ligand, dipicolyl-1,6-hexadiamine (Dipi) was conjugated to the Cterminus of vancomycin (Dipi-van) in our lab (20, Figure 11A).85 The idea was that the dipicolyl amine moiety would capture zinc ions (Zn2+), which could be released from apoptotic cells at the site of bacterial infection with high selectivity. The Dipi-van-Zn2+ could then complex with the pyrophosphate of the cell membrane lipids (Figure 11B). The enhanced inhibition of cell-wall biosynthesis was confirmed by the intracellular accumulation of the precursor, UDP-Nacetylmuramyl-pentadepsipeptide (UDPMurNAc-pp) (Figure 11C). Dipi-van exhibited a 375-fold and 160-fold increase in activity against VREm (VanA phenotype, E. faecium) and VREs (VanB phenotype, E. faecalis) as compared to vancomycin, respectively (Figure 11A). Further, this compound reduced the bacterial burden in mice in VRE kidney infection (5 log CFU g−1 reduction). It did not show any increase in MIC when bacteria were subjected to serial passages of the compound indicating no susceptibility to resistance development. Furthermore, components of the cell wall like the saccharides can also be targeted to enhance the activity of the drug. In another approach to enhance activity by targeting other components of the cell wall, Zhang et al. tethered a benzoxaborole group to the C-terminus of vancomycin, eremomycin, and teicoplanin aglycons, as well as to vancomycin, or to the N-terminus of vancomycin and teicoplanin aglycon, or M
DOI: 10.1021/acs.jmedchem.8b01093 J. Med. Chem. XXXX, XXX, XXX−XXX
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Table 2. Strategies To Tackle Intrinsic Resistance of Gram-Negative Bacteria to Vancomycin strategy
examples
activity
refs
A. baumannii-R4942 (MIC = 3 μM) E. cloacae: NDM-1 (MIC = 12.5 μM) P. aeruginosa-R590 (MIC = 6.1 μM)
90
•employment of silver (Ag+) as an adjuvant with vancomycin •polymyxin−tobramycin hybrids as adjuvant with vancomycin •colistin as an adjuvant with teicoplanin •colistin as an adjuvant with telavancin •nitrofurantoin as an adjuvant with vancomycin •trimethoprim as an adjuvant with vancomycin
90% survival of mice in an acute mouse peritonitis E. coli infection model P. aeruginosa (MIC of vancomycin reduced to 0.5 μg mL−1)
91
A. baumannii (MIC of teicoplanin ≤2 μg mL−1) MIC of telavancin
