Combating a Master Manipulator: Staphylococcus aureus

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Combating a Master Manipulator: Staphylococcus aureus Immunomodulatory Molecules as Targets for Combinatorial Drug Discovery Kadalipura P. Rakesh,† Manukumar H. Marichannegowda,*,‡ Shobhith Srivastava,§ Xing Chen,† Sihui Long,∥ Chimatahalli S. Karthik,‡ Putswamappa Mallu,‡ and Hua-Li Qin*,†

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Department of Pharmaceutical Engineering, School of Chemistry, Chemical Engineering and Life Science, Wuhan University of Technology, 205 Luoshi Road, Wuhan 430070, Hubei, P. R. China ‡ Department of Chemistry, Sri Jayachamarajendra College of Engineering, Mysuru 570006, Karnataka, India § Department of Pharmacology and Therapeutics, King George’s Medical University, Chowk, Lucknow 226003, India ∥ Key Laboratory for Green Chemical Process of Ministry of Education, Hubei Key Laboratory of Novel Reactor and Green Chemical Technology, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430073, Hubei, China ABSTRACT: Staphylococcus aureus is a bacterial pathogen that can cause significant disease burden and mortality by counteracting host defenses through producing virulence factors to survive the immune responses evoked by infection. This emerging drug-resistant pathogen has led to a decline in the efficacy of traditional antimicrobial therapy. To combat these threats, precision antimicrobial therapeutics have been created to target key virulence determinants of specific pathogens. Here we review the benefits of, progresses in, and roadblocks to the development of precision antimicrobial therapeutics using combinatorial chemistry. KEYWORDS: Staphylococcus aureus, combinatorial chemistry, precision antimicrobial therapeutics, pathogen defense, virulence factors

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INTRODUCTION Staphylococcus aureus (S. aureus) is a Gram-positive, nosocomial normal human microflora that causes common skin infections that result in 11−14 million outpatient visits and nearly 500 000 hospitalizations each year in the United States. S. aureus is responsible for 76% of all skin and soft tissue infections in community and healthcare settings. It is often difficult to treat S. aureus because of its resistance to widespread antibiotics, such as in the case of methicillinresistant S. aureus (MRSA).1 Figure 1 provides an example of the many ways bacterial pathogens resist and escape the defensive strategies of the host immune system. S. aureus produces many surface-anchored and secretary virulence factors, including peptides contributing to the inhibition of, or escape from, the innate immune response.2 For example, the bacteria secrete proteases to destroy specific components of the host immune system and also secrete proteins to bind precursors of host proteases that would otherwise attack the bacteria. Such host protease modulators include Coagulase (Coa) and von Willebrand factor-binding protein (vWbp), staphylokinase (SAK), α-toxins such as prothrombin, plasminogen, and a disintegrin and metal© XXXX American Chemical Society

loprotease 1 (ADAM1) activation, inhibitors such as extracellular adherence protein (Eap), super-antigen-like proteins 1 (SSL1) and 5 (SSL5), S. aureus collagen adhesin (Cna), staphylococcal complement inhibitor (SCIN), extracellular fibrinogen binding protein (Efb), serine aspartate glycosyltransferases A (SdgA) and B (SdgB), CP/LP C3 proconvertase, metalloproteases, C1 complex formation, AP C3 convertase, and human neutrophil-derived cathepsin G inhibitors.3 In addition, S. aureus adhesion during colonization and infection is also robust enough to counteract several host defense programs such as complement activation. Neutrophils are among the most important components of the immune defense mechanisms at local infection sites. They respond to chemotactic stimuli, which are identified by G protein-coupled receptors (GPCRs) such as formyl peptide receptor 1 (FPR1). The FPR1 recognizes formylated bacterial peptides, which are produced by bacterial protein biosynthesis using formylated methionine and are characteristic of bacterial Received: June 25, 2018 Revised: October 16, 2018 Published: October 29, 2018 A

DOI: 10.1021/acscombsci.8b00088 ACS Comb. Sci. XXXX, XXX, XXX−XXX

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ACS Combinatorial Science

Figure 1. Schematic network of how S. aureus counteracts the innate immune defense system. S. aureus colonizes the skin by neutralizing the acidic environment of human sweat via the production of ammonia (NH4+) from L-arginine catabolism. Greater colonization releases phenol-soluble modulins (PSMs) to recruit neutrophils, mast cells, and proteases to combat host defenses.

Figure 2. Different drug targets in S. aureus and clinical trials for discovering promising future antibiotic candidates.

infection. S. aureus counteracts this component of immune attack by producing FPR1, a chemotaxis-inhibiting protein (CHIP), to block formylated peptide recognition. In addition, S. aureus secretes a highly specific inhibitor of FPR1-related formyl peptide receptor 2 (FPR2/ALX, initially denoted formyl peptide receptor-like 1, FPRL1) of human neutrophils, the FPR2/ALX-inhibitory protein (FLIPr), and the reason for secretion of FLIPr by S. aureus has remained mysterious.4

Even though the physical pathways of infection have been established, it is still not understood how the skin commensal S. aureus virulence factors cause S. aureus to become virulent. Two quorum-sensing (QS) molecules, LuxS and Agr, are known in S. aureus.5 The master virulence (Agr-accessory gene regulatory) program is a two-component system responding to bacterial density and is involved in controlling the expression of phenol-soluble modulins (PSMs) (Figure 1). Among the seven PSMs, PSMα is highly cytotoxic to immune cells B


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Figure 3. Representative powerful antibiotics derived from aminoglycosides against S. aureus.

active drugs, and changing the membrane permeability to antibiotics.11,12 As a consequence, over the last few decades many pharmaceutical companies have started screening early-stage molecules against new targets and have invested a huge amount of money in such programs but have gained little success in treating multi-drug-resistant (MDR) pathogens.13,14 Thus the huge investments did not lead to profitable products, and, accordingly, many companies have exited this therapeutic area (Figure 2). Because of huge global burden of S. aureus and its epidemic nature, currently only a few antibiotic treatments are left, such as clindamycin,15,16 doxycycline,17 linezolid,15,18,19 trimethoprim/sulfamethoxazole (TMP/SMX),20,21 daptomycin,15,22−24 teicoplanin,25,26 vancomycin,15 and so on.

including keratinocytes, but which secretary factor is responsible and the mechanism by which S. aureus counteracts keratinocytes remain unknown.6 To prevent serious infections, neutrophils function by releasing various neutrophil serine proteases (NSPs) such as neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CG) upon NSP activation from stored azurophilic granules. These NSPs cleave secreted virulence factors, receptors, and chemokines to regulate immune response to the pathogen.7,8 S. aureus produces serine-protease-like (spl) virulence factors as well via the spl operon on the vSaβ pathogenicity island, which carries six serine protease genes (splA to splF). Staphopain A (ScpA) and staphopain B (SspB) are cysteine and serine proteases and are able to combat the host immune system by attacking the N-terminal domains of CXCR2 and CD31, respectively.3 These secreted molecules inhibit the neutrophil serine proteases involved in ending the journey of S. aureus in the host, and also extracellular adherence protein (Eap) homologues EapH1 and EapH2 act as a unique class of noncovalent inhibitors in the nanomolar range as manipulators of the immune system and innate immunity8 (Figure 1). Apart from these interactions, the pathogen takes advantage of becoming resistant to antibiotic effects. In this regard, it is necessary to understand the multifactorial counteracting mechanism by this pathogen, and also design strategies for developing drugs to specific targets are needed.7 The urgency of antibiotic discovery and its role in combating the rise of antimicrobial resistance has emerged as a global challenge in modern medicine, as we aim to prevent the ultimate death of people infected by even common bacteria. Many antibiotics are developed for clinical use targeting bacterial cell−wall synthesis, DNA replication, folic acid metabolism, membrane structure, and protein synthesis to avoid resistance.9 However, MRSA currently is resistant to standard-of-care (SOC) drugs, and their clinical utility in the future is drastically diminished by the accessible targets in MRSA.10 Many factors cause MRSA to become resistant through horizontal transfer of genes, such as acquiring drug-resistant targets (biofilm-forming genes, β-lactamase genes, and ion channel genes) by bypass mechanisms, and mutations (Figure 2). Four key mechanisms of antibiotic resistance developed by MRSA include efflux pump, alteration in drug target, enzymatic hydrolysis of the

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COMBINATORIAL STRATEGY: DISCOVERY AND DEVELOPMENT OF NEW ANTIBIOTICS From the early 1960s through the 1970s, many antibiotics were developed using natural sources and chemicals via a semisynthetic approach. As a consequence of the over/misuse of broad-spectrum antibiotics, drug-resistant bacteria emerged within a short period of time. With advancements in molecular biology, bacterial genome analysis, and targeted drug discovery by combinatorial chemistry approaches, a number of promising lead compounds were identified and optimized as potential targets. According to FDA, because of bacterial resistance, the approved drugs are losing their efficacy to resistant bacterial strains, and to overcome this problem in treating infectious bacteria, new drug designing approaches are needed for future treatment.27 But after decade-long efforts, expected results did not become a reality for several reasons, including: (i) the inability of the lead compounds to cross the bacterial cell wall and (ii) the narrow spectrum of the biocidal lead compounds did not meet required criteria for further development. The pharmaceutical companies primarily focused on developing broad-spectrum antibiotics due to financial incentives. This critical fiscal goal in drug discovery leads to a quest for “blockbuster drugs”, that is, drugs generating more than $1 billion of revenue yearly. In this regard, new combinatorial approaches are needed to design promising and efficient druglike candidates, which are used for clinical trials in future to treat bacterial infections. C


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ACS Combinatorial Science Table 1. Derivatives of the 2-Deoxy-streptamine Used for the Synthesis of Antibiotics 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

antibiotics

R1

R2

R3

R4

R5

R6

R7

R8

R9

R10

kanamycin A kanamycin B tobramycin dibekacin amikacin arbekacin isepamicin gentamicin B gentamicin C1 gentamicin C2 gentamicin C1A

H H H H H H H H CH3 CH3 H

H H H H H H H H CH3 H H

OH OH OH H OH H OH OH H H H

OH OH H H OH H OH OH H H H

OH NH2 NH2 NH2 OH NH2 OH OH NH2 NH2 NH2

H H H H COCHOH(CH2)2NH2 COCHOH(CH2)2NH2 COCHOHCH2NH2 H H H H

H H H H H H H CH3 CH3 CH3 CH3

H H H H H H H OH OH OH OH

OH OH OH OH OH OH OH CH3 CH3 CH3 CH3

CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH CH2OH H H H H

deoxy-tobramycins [16−19] showed potent nature against S. aureus (Figure 4, Table 2).37

The majority of aminoglycoside antibiotics are isolated from soil bacteria streptomyces and acetinomycetes species. After penicillin, streptomycin [1] is the second antibiotic that was employed in clinical trials, whereas it was the first drug in the class of aminoglycoside isolated in 1944 by Waksman.28,29 In 1949, Waksman identified neomycin [14], but because of its poor bioavailability, cell penetration, and toxicity, it is only used in topical applications. Kanamycin [3] was identified in 1957, and it was widely used until the discovery of gentamicin [2]. Gentamicin was isolated in 1963 from Micromonospora, and it was a clinically successful candidate. After the success of gentamicin, researchers were interested in searching for similar antibiotics and identified some of them such as tobramycin [5], dibekacin [6], amikacin [7], arbekacin [8], isepamicin [9], gentamicin B [10], gentamicin C1 [11], gentamicin C2 [12], and gentamicin C1A [13]. Aminoglycoside antibiotics of 2deoxy-streptamine derivatives attached to 4,5,6-substitutents of amino sugars are powerful broad-spectrum antibiotics that target a rRNA helix of the mRNA−tRNA decoding center of the bacterial 30S ribosomal subunit,30−32 thus affecting the accuracy of bacterial translation and causing inhibition of cell growth. These antibiotics specifically bind to the functional RNA-A decoding site (Figure 3, Table 1).33−36 Because of increased bacterial resistance to aminoglycosides, a new approach leads to semisynthetic glycosides in which amikacin [7] is the first in class clinically tested. After streptomycin use against Mycobacterium tuberculosis and penicillin as a second compound employed for the therapy, subsequent compounds are also developed, such as neomycin [14] used for tropical application due to poor bioavailability and paromomycin [15] not used systematically due to poor potency.37

Figure 4. Combinatorial approaches for tobramycin derivatization.

Table 2. Derivatives of Tobramycin Antibiotic from a Deoxy Generation Approach 5 16 17 18 19

compounds/derivatives

R1

R2

R3

R4

tobramycin 4′-deoxy-tobramycin 2′-deoxy-tobramycin 4″-deoxy-tobramycin 6-deoxy-tobramycin

OH H OH OH OH

OH OH H OH OH

OH OH OH H OH

OH OH OH OH H

S. aureus becomes resistant to the aminoglycosides due to the decrease in drug uptake, accumulation, and expression of the bacterial enzymes to modify the antibiotic to inactivate it and many other reasons (Figure 2).38,39 There is a need for understanding how to design a drug to escape the modifying enzymes that are involved in the bacterial resistance. Some of the bacterial enzymes modify the aminoglycosides by catalyzing the covalent modification at specific amino and hydroxyl functions, which leads to modifying the drug and the energy-dependent phase II (EDP-II) accelerated drug uptake. The enzymes modifying aminoglycosides include N-acetyltransferases (AAC), which use acetyl-coenzyme A as the donor and affect amino functions, and O-nucleotidyltransferases (ANT) and O-phosphotransferases (APH), which both use ATP as the donor and affect hydroxyl functions. The functions affected in typical aminoglycosides (kanamycin and gentamicin derivatives) are on positions3, 2′, and 6′ for AAC, positions 4′ and 2″ for ANT, and positions 3′ and 2′′ for APH (Figure 5).40 To design a successful desired active compound against aminoglycoside-modifying enzymes, we need to combine the approaches of known conventional pharmacology, structure− activity relationship (SAR), and medicinal chemistry to explore the powerful candidates against a broad range of infections causing bacteria, and novel approaches to be applied in the same line of antibiotics are currently working. To understand the exchange of chemical moieties to escape the resistancecausing enzymes, 2-deoxy-streptomycine was chosen to explain

The amino and hydroxyl groups of aminoglycoside antibiotics contribute to the binding site in RNA. To better understand the mechanism, tobramycin was deoxygenated in a combinatorial approach, and 4′-deoxy-, 2′-deoxy-, and 4″D


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Figure 5. Resistance causing aminoglycoside-modifying enzymes acting at kanamycin B. (This aminoglycoside is susceptible to drug modifying enzymes.)40

Figure 6. Chemical modifications performed on kanamycin B by specific aminoglycoside-modifying enzymes to cause resistance. (Check Figure 5 for the enzyme acting on each position.)

On the basis of a report from Hanessian et al.,41 a semisynthetic 4,6-disubstituted 2-deoxystreptamine candidate, such as arbekacin, was found to overcome the action of a subset of the aforementioned enzymes used by S. aureus against active components of aminoglycosides.46 To overcome the drug-resistance strains of MRSA, they synthesized derivatives of arbekacin, and among them 5,4″-diepi-arbekacin (TS2037) emerged as the most potent antibacterial agent against S. aureus, having an minimum inhibitory concentration (MIC) value of 0.25 μg/mL compared with arbekacin’s 0.25 μg/mL (Figure 8). Even though many anti-MRSA drugs are in the clinical investigations, in which aminoglycoside TS2037 is the one promising lead candidate as an antimicrobial, further interest in aminoglycoside research may find a way into further evaluation.47 Many types of compounds48 are investigated in the clinical research pipeline as candidates against drug-resistant MRSA

the combinatorial approaches to design a novel target molecule (Figure 6).38 Hanessian et al.41 showed that the class of 4,5-disubstituted 2-deoxystreptamine aminoglycosides, including butirosin, paromomycin, and neomycin, shares a common binding site, mode-of action, and powerful biocidal properties. But they were never used as anti-infectives due to their susceptibility to multiple enzymes that modify their structure. The most prominently used class for clinical purposes belongs to 4,6disubstituted 2-deoxystreptamine, including gentamicin, tobramycin, amikacin, isepamicin, and arbekacin. Because of continuous use, S. aureus becomes resistant to the above drugs due to the emergence of modifying enzymes, prevalently 4′-Onucleotidyltransferase, ANT(4′)-I, 3′/5″-O-phosphotransferase, APH(3′/5″)-III, and the bifunctional 2′′-O-phosphotransferase and 6′-N-acetyltransferase, APH(2″)/AAC(6′), whose respective target preferences are shown in Figure 7.42−45 E


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taining β-lactams, and (5) S649266. (C) New cephalosporins and β-lactams that have activity against β-lactamase and carbapenemase-producing bacteria. The compound S649266 (Phase 3 development: CREDIBLE-NCT02714595) showed β-lactamase inhibition, but it is not used in combination with β-lactamases inhibitors; it is highly active against Gramnegative bacteria. (D) New pleuromutilins: Lefamulin (BC3781) is a semisynthetic compound effective against MRSA by inhibiting the bacterial protein machinery (Phase 3 development: CABP-NCT02813694). (E) New tetracycline: Omadacycline is a tetracycline derived in a subclass called aminomethylcycline for the treatment of acute bacterial skin and skin structure infection (ABSSSI) (Phase 3 development enrolled: NCT02531438). (F) New macrolides: The solithromycin phase 2/3 pivotal trial (NCT02605122) in pediatric patients (2 months to 17 years of age) with CABP has been initiated. (G) New fluoroquinolones and DNA gyrase inhibitors: Delafloxacin (completed two Phase 3 trials known as “PROCEED” in which the comparator was vancomycin + aztreonam: NCT02679573) against ABSSSI. (H) New o x a z o l i d i n o n e s : C a d a z o li d ( P h a s e 3 : I M P A C T : NCT01987895), MRX-1 (Phase 2: NCT02269319), and sutezolid (Phase 2: NCT01225640). (I) New fatty acid biosynthesis inhibitors: Debio1452 is a type of Fab1 inhibitor, active against all resistant staphylococcal strains by inhibiting enoyl-acyl carrier protein reductase (Phase 2: NCT02426918) and CG400549 another inhibitor (Phase 2: NCT01593761) for the treatment of ABSSSI caused by MRSA. (J) New folate biosynthesis inhibitors: Iclaprim is a type of diaminopyrimidine and next-generation inhibitor of dihydrofolate reductase (DHFR) (Phase 3 development: NCT02607618) against ABSSSI of MRSA and MSSA showing low propensity to develop resistance in bacteria. (K) Defensin: mimetic peptides: Brilacidin (Phase 2 studies: NCT02052388) against ABSSSI of MRSA including nondividing bacterial cells by acting on cell membrane and without altering the cell membrane of mammalian cells causing cytotoxicity. Only a few of these candidates receive approval at the end of Phase 3 trials. All of the above candidates are modified versions of known compounds that have previously shown antibacterial actions so far.9 Efforts to identify novel lead candidates via combinatorics for chemical biology investigations and drug discovery programs are underway. Through one such approach, Nicolaou et al.49 designed a combinatorial library of 65 new benzopyranderived cyanostilbenes (MIC < 50 μg mL−1) against MRSA strains. Structure−activity relationship (SAR) studies identify the stilbene moiety orientation on the benzopyran ring system as the reason for the potency of analogs 20 > 21 > 22 (MIC 3, 12, and 13 μg mL−1 respectively) (Figure 9). Second, the free phenolic moiety at the terminal aromatic ring confers its potency compared with the original >1000 members in the stilbene library containing other substituents such as ethers, esters, halogens, nitro groups, sulfonates, and heterocycles, which are inactive at the original concentrations (MIC < 50 μg mL−1). In light of the above evidence, benzopyran 20 was selected as a promising lead for further systematic investigation, and 62 analogs were constructed. For example, the SAR shows the reduction of the pyran moiety of 20 in the saturated counterpart of analog 27 (MIC 3 to 4 μg mL−1) led to indistinguishable antibacterial potency. Even though the analog 27 is not identical to analog 20, this may be due to the lack of a

Figure 7. Representative members of the 2-deoxystreptamine aminoglycoside classes characterized by 4,6-disubstitution (amikacin and gentamicin C1) or 4,5-disubstitution (neomycin B). Arrows indicate the positions targeted by modifying enzymes prevalent in S. aureus (black, complete resistance; gray, medium resistance; white and crossed, evaded).

such as: (A) New aminoglycosides: plazomicin (Phase 3 currently underway: NCT01970371) against MDR Enterobacteriaceae. (B) β-lactamases, cephalosporinase, and carbapenemase inhibitors in combination with old and new βlactams such as (1) avibactam, (2) ceftolozane, (3) vaborbactam (RPX7009), (4) relebactam, siderophore-conF


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Figure 8. Chemical structures of TS2037 (A) and arbekacin (B).

Figure 9. (A) Structures and antibacterial activities of lead compounds 20, 21, and 22 identified from combinatorial libraries. (B) Synthesis of benzopyran stilbene analog 27: (a) methyltriphenylphosphonium bromide (1.1 equiv), n-butyllithium (1.1 equiv), THF, 0 to 25 °C, 12 h, 80%; (b) 4-OTHP-bromobenzene (25) (1.1 equiv), [Pd2(dba)3] (0.1 equiv), P(o-tolyl)3 (0.12 equiv), DMF, 90 °C, 12%; (c) p-TsOH′H2O (0.5 equiv), THF/MeOH (10:1, v/v), 25 °C, 1 h, 100%. [Pd2(dba)3] = tris(dibenzylideneacetone)dipalladium(0), P(otolyl)3 = tri-o-tolylphosphane.

nitrile group on the stilbene olefin part, indicating that the α,βunsaturated nitrile moiety has no functional role in the activity of this compound. This interesting result confirms that these types of compounds do not gain biological activity through an electrophilic mechanism. For future development, this research group suggests that this series of analogs can be modified with an unsubstituted stilbene bridge (like analog 27) to avoid potential toxicity. These results from the indiscriminate electrophilicity of the α,β-unsaturated nitrile functionality and the future drug discovery program highlight the need for improvement in the pharmacological profile during MRSA infections (Figure 9). The discovery of new synthetic routes for a small library of biarylhydroxyketones as candidates against MRSA by Yu et al.50 through Friedel−Crafts acylation between analogs 28 and 29 generated a combinatorial 148 individuals in the study,

using R1 (5-H, 5-ethyl, 6-OH, 5-methyl, 5-propyl, 5-hexyl) and R2 (F, Cl, Br, I, NO2, Me, i-Pr, Ph, COOH, t-Bu, OCH3, COOCH3) groups in the generated analogs. Among them, analog 32 showed bacteriostatic and antivirulence dual activity (Figure 10). The hemolysis inhibition activity was attributed to the large hexyl chain at the five-position of the resorcinol ring in addition to the presence of two fluorine atoms on the aryloxy portion of this analog. Furthermore, this analog inhibited the binding of AgrA to its DNA, in turn, inhibiting the production of the α-toxin from MRSA involved in the host hemolysis.51 Interestingly, blocking the expression of the virulence agents in MRSA enables host defense factors to act during infection. The rapid increase in bacterial resistance due to currently used antibiotics and the lack of potent new candidates to combat antimicrobial resistance (AMR) create a major G


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Figure 10. Synthesis of a biarylhydroxyketone library through Friedel−Crafts acylation between 28 and 29 and potent biarylhydroxyketone 32.

Figure 11. Highly potent natural teixobactin 33 (A,B) synthesis of D-arg4-leu10-teixobactin (34) starting from a 2-chlorotrityl chloride resin. (a) Fmoc-Ala-OH (4 equiv) and DIPEA (8 equiv) in DCM, 3 h. (b) Piperidine (20%) in DMF followed by 3 equiv of AllocHN-D-Thr-OH and 3 equiv of HATU with 6 equiv of DIPEA, 1.5 h. (c) Fmoc-Ile-OH (10 equiv), DIC (10 equiv), and 5 mol % DMAP in DCM, 2 h, followed by a capping with Ac2O/DIPEA 10% in DMF and 20% piperidine in DMF. (d) Fmoc-Leu-OH (4 equiv) and HATU (4 equiv) with DIPEA (8 equiv) in DMF, 1 h, followed by 20% piperidine in DMF. (e) Trt-Cl (10 equiv) and 15% Et3N in DCM, 1 h. (f) [Pd(PPh3)4]0 (0.2 equiv) and PhSiH3 (24 equiv) in dry DCM, 1 × 20 min and 1 × 45 min. (g) Fmoc/Boc−AA(PG)−OH (4 equiv, AA = amino acid, PG = protecting group), DIC/Oxyma (4 equiv, MW, 10 min), followed by 20% piperidine in DMF (3 and 10 min). (h) TFA/TIS/DCM 2:5:93, 1 h. (i) HATU (1 equiv) with DIPEA (10 equiv) in DMF, 30 min. (j) TFA/TIS/H2O 95:2.5:2.5, 1 h. H


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Figure 12. New antibiotics in drug discovery and clinical trials with new mechanism of actions. (A) ACHN-975, (B) brilacidin, and (C) delafloxacin.

following, three important candidates are discussed to highlight their upcoming promise against drug-resistant diseases. Analog 35 (ACHN-975, a Phase 1 candidate from Achaogen) is a new class of antibacterial candidate (Figure 12A). It inhibits LpxC, an enzyme involved in lipid biosynthesis in Gram-negative bacteria (Enterobacteriaceae: Pseudomonas aeruginosa) and inactive against Gram-positive bacteria.54 Analog 36 (Brilacidin, PMX-30063, a Phase 2 candidate from Cellceutix) is a nonpeptide chemical mimetic (Figure 12B) and an investigational new drug (IND) representing a new class of synthetic (arylamide foldamer) mimetics of host defense proteins, which is the first line of defense against microbial infection in many species, including “superbug” MRSA. Brilacidin showed less cytotoxicity to mammalian cells through selectively targeting the bacteria by direct disruption of the membrane to cause its death. Because of its unique mechanism and novel action of mimicking the host innate immune response (first time proven to be successful in fighting against infections evolved over millions of years), this new drug is less likely to become bacteria-resistant.55−58 Analog 37 (delafloxacin (DLX) (Figure 12C)) is a recent (July 2017) U.S. Food Drug Administration (FDA) approved drug with the trade name BAXDELA. It possesses excellent broad spectrum activity against clinically relevant bacteria including MRSA and MSSA, which cause ABSSSI in skin. DLX operates in a biological system by changing its potent character in response to pH, immune defense, pathogenic counteracting mechanisms, and circulating environments. The C7 basic group in DLX acts as a zwitterion and is distributed inside of the phagolysosome (pH 5 to 5.5). The subsequent deprotonation of DLX helps retain bacteria in host.59 DLX has been used as a fourth-generation fluoroquinolone (FQ) and as dual DNA gyrase (topoisomerase II) and topoisomerase IV inhibitor to shut down the growth of S. aureus by

challenge to global health. An estimate of 10 million deaths every year and $100 trillion in lost productivity to the global economy by 2050 has been predicted. To establish a new horizon in drug development against resistant bacteria, very recently, Parmar et al.52 discovered a natural product, teixobactin (analog 33), with remarkably broad activity against Gram-positive bacteria, including MRSA, vancomycin-resistant enterococci (Enterococcus spp., VRE), and Mycobacterium tuberculosis. This nonribosomal teixobactin is an undecapeptide containing four amino acids, namely, N-Me-D-Phe1, D-Gln4, Dallo-Ile5, D-Thr8, and the rare L-allo-enduracididine amino acid (marked in red and blue, respectively). It killed MRSA (MIC = 0.25 μg/mL) without detectable resistance and is less likely to be susceptible to resistance because it binds to highly conserved pyrophosphate motifs of multiple bacterial cell-wall substrates, such as lipid II, a precursor of peptidoglycan, and lipid III, a precursor of cell-wall teichoic acid.53 Parmer and coworkers52 synthesized another 10 highly potent derivatives of teixobactin. Among them, analog 34 (D-Arg4-Leu10teixobactin) (Figure 11) is promising against MRSA (>99.0%), and its noncytotoxic nature confers a high therapeutic value in attenuating bacterial infections. This further calls for more novel molecules to be synthesized against MRSA in combinatorial approaches for future antibiotic drug discovery.

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WORKING TOWARD DISCOVERING NEW DRUG MECHANISMS The Pew Charitable Trusts reported that nearly all of the antibiotics approved from the last three decades are modified forms of the already known classes of robust compounds against resistant bacteria. Currently, the special mechanism of action against resistant microbial candidates is understood for only a few antibacterial candidates (Figure 12). In the I


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developed counteracting mechanisms by overcoming drug resistance, is an upcoming new target-based approach in drugdiscovery programs. The commonly used antibiotics today were discovered during the “Golden Age” of antibiotics, and they are the first and most successful class of drug candidates that can treat a broad spectrum of targeted infections. These types of antibiotics have lost their patent protection and have been used as generic, low-priced drugs. This has led to their overuse, misuse, and the evolution of antibiotic resistance. In turn, this has drawn the attention of infectious diseases specialists.13 The resulting global burden has spurred large pharmaceutical companies to redirect resources to develop drugs to overcome the problem of resistance in medicines. To combat real threats, increasing effort is being focused to develop precision antimicrobial therapeutics that target key virulence determinants of specific pathogens such as S. aureus63 while leaving the remainder of the host microbiota undisturbed. Because of the nonspecificity of the current antimicrobials, “superbug S. aureus” can take advantage of the present antibiotics and is predicted to kill more than 10 million each year by 2050.64 Also, World Bank suggests that by 2050 the consequences of elevated antibiotic-resistant infections could cost the world economy an estimated $100 trillion.65 To address this emerging crisis, current research focuses on elucidating the destructive property of broad-spectrum antibiotic treatment on the beneficial host microbiota. These new types of therapeutics, hitherto called “precision antimicrobials”, include both new antivirulence compounds to inhibit bacterial pathogenesis and persistence and bacteriostatic/bactericidal compounds to minimize bacterial pathogens. Very recently, a commensal strain Staphylococcus lugdunensis has selectively removed and inhibited the metabolism of S. aureus by producing a natural compound called “lugdunin” (a cyclic peptide), but its precise mechanism of action remains unknown.66 Like this, many promising inhibitors are uncovered, having an attenuated role against S. aureus pathogenesis through lipoteichoic acid synthesis, RnpAmediated RNA degradation, sortase activity, and iron−sulfur cluster assembly. These examples shed light onto the microbial world of small-molecule-based treatment approaches.67−70

deactivating the prime functions of cell growth by interfering with cell DNA replication, transcription, repair, and recombination.60 DLX also has significant activity in acidic media compared with other quinolones against S. aureus, which has resistance to quinolones; in the future, drug discovery programs will concentrate on developing drug-like candidates to overcome the resistance problem associated with diseases.

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IS S. aureus 100S RIBOSOME RESPONSE IMPORTANT FOR FUTURE THERAPEUTIC DISCOVERY AGAINST THE SLEEPING FACTOR OF S. aureus? Hibernating Factors Are the Perfect Targets! The bacterial 30S and 50S subunit ribosomes are extensively studied cellular components involved in translating a universal code into proteins in the 70S complex. The 100S ribosome is ubiquitously found in all bacterial phyla (Figure 2). A common feature of all biological processes is the conservation of energy because protein synthesis accounts for >50% of energy cost. This study reveals that the lack of any 100S ribosome makes cells prone to suicide due to rapid degradation of ribosomes. The hibernation-promoting factor (HPF) is involved in the homodimerization of the 100S ribosome, which is a translationally silent complex. The 100S ribosome is of temporal abundance in different phyla; however, the regulation and disassembly of 100S ribosome is unknown.61 In Escherichia coli (E. coli), 100S dimers were found in a stationary phase when nutrient was scarce, but in S. aureus, the 100S dimer was found throughout all phases, including nutrient -rich ones. In addition, studies have suggested that the formation of 100S dimer during the logarithmic growth phase of S. aureus is responsible for the shutdown of the translational efficacy of a few genes and the loss of HPF, demonstrating massive ribosome degradation entering the stationary phase, which correlates with the rate of cell death. In E. coli, three ribosome-silencing factors (YfiA inactivates the 70S and recycles to translation; RMF, ribosome modulation factor; and HPF, dimerization of 100S into inactive 100S complex) are related to binding the ribosome subunit and blocking the binding of mRNA (mRNA) and the anticodon region of A-, P-, and E-tRNA (tRNA). However, the absence of RMF or YfiA in S. aureus hpf gene codes another form of HPFSA, which is twice the size of HPFEC with dual functions as N-terminal HPFSA to block the mRNA and as anticodon tRNA binding site. These interesting highlights demonstrate that understanding of the distinct 100S structure of the S. aureus compared with E. coli complex may be a potential and novel species-specific therapeutic target and the best strategy to unlock the pathogenesis.61,62 Matzov et al.61 reveal that even though the 100S complexes in gammaproteobacteria and Gram-positive bacteria serve the same functions, their dimerization and structural orientation are different. The unique interaction of HPF with 100S and the hampering of the complex formation by targeting their unique signature between twin ribosome emphasize the distinctive Gram-positive specific antibacterial treatment (Figure 2). In the future, strategies to overcome and counteract the S. aureus mechanisms during pathogenic conditions are warranted.

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CONCLUSIONS The emergence of drug-resistant pathogen MRSA through counteracting the host immune system and declining traditional antibiotic therapy by misuse have caused a rise in the resistance to broad-spectrum antibiotics. To combat this threat, the challenges lie in the development of precision candidates such as texiobactin and vancomycin that target key virulence determinants of specific pathogens while they leave other microbiota undisturbed. These candidates face a traditional hurdle in development processes such as bioavailability, toxicity, and manufacturing scalability. In traditional antibiotics, the scope is broad by targeting the core bacterial process common in all strains in a group to avoid crossreactivity with host cellular process. In contrast, the precision antimicrobials designed to target specific bacteria occur only in a defined subset of pathogens, without affecting either the host or the beneficial bacteria within the microbiota. Developing therapies that target the host reservoir of pathogens, rather than simply the site of infection, may help reduce disease burden or prevent recurrence. To which, the “precision” or “ultra-narrow” candidates are tailormade as a result of understanding the various stages of the pathogen lifestyle.

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PRECISION IN TARGET DRUG DISCOVERY The development of precision drugs to wipe out bacterial bugs during the pathogenic state in the body, protected by its wellJ


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The design of therapeutics that disrupt the critical pathways in virulent pathogens such as MRSA is warranted and represents the “future” of overcoming the resistance problem.

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AUTHOR INFORMATION

Corresponding Authors

*M.H.M.: E-mail: [email protected]. Fax: +918884354447. *H.-L.Q.: E-mail: [email protected]. Fax: +86 27 87749300. ORCID

Kadalipura P. Rakesh: 0000-0001-9317-8462 Manukumar H. Marichannegowda: 0000-0002-6488-7136 Sihui Long: 0000-0002-4424-6374 Hua-Li Qin: 0000-0002-6609-0083 Author Contributions

The technical content was designed and the manuscript was written by M.H.M., suggestions were given by H.L.Q. and P.M., corrections were edited by K.P.R., S.S., S.L., and C.S.K., and references were checked by X.C. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful to the National Natural Science Foundation of China (Grant No. 21772150), the Wuhan Applied Fundamental Research Program of Wuhan Science and Technology Bureau (Grant NO. 2017060201010216) and Wuhan University of Technology for the financial support.

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Combating a Master Manipulator: Staphylococcus aureus

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