Chem. Pharm. Bull. 68(3): 182-190 (2020)

182 Chem. Pharm. Bull. 68, 182–190 (2020) Vol. 68, No. 3 Current Topics

Drug Discovery: Recent Progress and the Future

Review

Potent Antibiotics Active against Multidrug-Resistant Gram-Negative Bacteria

Yasunari Otsuka Institute of Microbial Chemistry (BIKAKEN), Numazu; 18–24 Miyamoto, Numazu, Shizuoka 410–0301, Japan. Received September 26, 2019

The emergence of multidrug-resistant (MDR) Gram-negative bacteria has become a global problem. Among MDR Gram-negative bacteria, carbapenem-resistant Enterobacteriaceae (CRE), MDR Pseudomo- nas aeruginosa, and MDR Acinetobacter baumannii have limited treatment options and present serious threats. Therefore, strong countermeasures must be taken against these bacteria immediately. Accordingly, the focus of this review is on recent advances in the development of promising antibacterial agents against MDR Gram-negative bacteria. These agents include novel tetracyclines, polymyxins, β-lactams, β-lactam/β- lactamase inhibitors, aminoglycosides, and peptide mimetics that have been recently approved or have shown promising results in clinical and preclinical development. This review summarizes these potent antibiotics in terms of their development status, mode of action, spectra of activity, and structure–activity relationship. Key words antibiotic; drug candidate; Gram-negative bacteria; carbapenem-resistant

1. Introduction To combat MDR Gram-negative bacteria, innovative ap- The emergence of multidrug-resistant (MDR) Gram-neg- proaches, including the rational design of drug structures and ative bacteria has become a global concern.1–3) Accordingly, the discovery of novel mechanisms of action, are desperately MDR Gram-negative bacteria have been defined as prob- needed. As of June 2019, approximately 42 new antibiotics lematic pathogenic bacteria by the United States Centers for were in clinical development.14,15) Of these, one-third exhibit Disease Control and Prevention (CDC) and by WHO. In 2013, potent antibacterial activity against any of CRE, carbapenem- the United States CDC declared that carbapenem-resistant resistant A. baumannii, and carbapenem-resistant P. aerugi- Enterobacteriaceae (CRE),4) as well as drug-resistant Neisseria nosa. gonorrhoeae and Clostridium difficile are an urgent threat Recently, several excellent reviews of antibiotics have been to public health.5) Furthermore, WHO recently published its published, including those on antibiotics in the late clinical “priority list of antibiotic-resistant bacteria for R&D.”6) This pipeline and in development,16,17) on treatment options for list classified carbapenem-resistant Acinetobacter baumannii, MDR Gram-negative bacteria,18) and on the strategic opti- carbapenem-resistant Pseudomonas aeruginosa,7) and carbape- mization of structure.19,20) This review summarizes current nem-resistant extended spectrum β-lactamase (ESBL)-pro- potent antibiotics active against dangerous Gram-negative ducing Enterobacteriaceae as “Priority 1: critical.”8,9) This list bacteria in terms of their development status, mode of action, demonstrates that the development of antibiotics active against spectra of activity, and structure–activity relationship (SAR). MDR Gram-negative bacteria, particularly carbapenemase- producing organisms, is key to preventing future catastrophic 2. Novel Tetracycline-class Antibiotics for MDR Gram- pandemic outbreaks. Therefore, strong countermeasures must negative Bacteria be taken against these bacteria immediately. Tetracycline antibiotics derived from natural products do Carbapenemases are enzymes that break down carbapenems not contain substituents at the C-7, C-8, and C-9 positions. via hydrolysis of the β-lactam ring. Of these enzymes, Kleb- However, the development of totally synthetic methods to siella pneumoniae carbapenemase (KPC) and the New Delhi synthesize tetracyclines has made it possible to modify these metallo-β-lactamase-1 (NDM-1) are the most problematic three positions,21,22) providing novel and fully synthetic tetra- enzymes.10) To make matters worse, carbapenemase-producing cyclines such as X ER AVA and TP-6076, developed by Tet- organisms frequently exhibit resistance mechanisms toward raphase Pharmaceuticals Inc. (Fig. 1). The introduction of an common antibiotics, including fluoroquinolones, tetracyclines, electron-withdrawing group at the C-7 position, and substitu- and aminoglycosides. Consequently, there are limited treat- tion at the C-9 position, significantly improved the antimicro- ment options for carbapenemase-producing organisms.11) This bial activity of these synthetic tetracyclines.23,24) situation has led to the reintroduction in clinical practice of XERAVA (eravacycline, TP-434)25–27) was the first fully the old and potentially toxic antibiotic colistin as a last resort synthetic fluorocycline produced by Michael-Dieckmann reac- for the treatment of Enterobacteriaceae-producing KPC and tion.28) XERAVA was approved by the U.S. Food and Drug NDM-1.12,13) Administration (FDA) in August 27, 2018 for the treatment of

Fig. 1. Structures of XERAVA, TP-6076, and Tigecycline

Fig. 2. Structures of SPR206 and SPR741 complicated intra-abdominal infections (cIAIs) in adults.29–31) disrupt the outer membrane of Gram-negative bacteria.51) The XERAVA exhibits broad-spectrum activity against Gram- SAR study demonstrated that the position of the amino group positive, Gram-negative, and anaerobic bacteria that have in the side chain affected antimicrobial activity and cytotoxic- acquired tetracycline-specific efflux and ribosomal protection ity.52,53) Replacement of the side chain of polymyxin-B with mechanisms.32,33) Furthermore, XERAVA demonstrates po- an aminobutyrate unit improved the safety and tolerability of tency against MDR bacteria producing ESBL, carbapenemase, SPR206 compared with those of colistin.54) SPR206 is being and A. baumannii.34–37) In vitro antimicrobial tests demonstrat- evaluated in phase I clinical trials and has acquired qualified ed that XERAVA is 2- to 4-fold more potent than tigecycline38) infectious disease product (QIDP) status. against Gram-positive and Gram-negative bacteria. The in SPR741 (formerly NAB741) was designed to minimize the vivo efficacy of XERAVA utilizing murine thigh infection nephrotoxicity of the polymyxin group, and it has completed models was established.39–41) phase Ia and Ib trials. SPR741 retains the ability to permeate TP-6076 is currently being evaluated in phase I trials. SAR the outer membranes of Gram-negative bacteria. Furthermore, studies of the C-4, C-7, and C-8 positions demonstrated that its safety profile is improved compared to that of polymyxin- 55,56) electron-withdrawing CF3 and OCF3 groups at the C-7 posi- B. Development of a drug to treat Gram-negative bacteria tion resulted in appreciable activity.42,43) In the case of the has previously been obstructed by the inability to penetrate C-8 position, pyrrolidine resulted in better activity than 4- or the bacterial outer membrane. However, this problem has been 6-membered cyclic amines or N-Me pyrrolidine. Finally, the mitigated by using a potentiator agent that permeabilizes the C-4 position tended to prefer small aliphatic tertiary amines, outer cell membrane. SPR741 potentiates the activity of co- with the diethylamino analog showing the best antimicro- administered antibiotics against Gram-negative bacteria,57,58) bial activity.44) TP-6076 inhibits bacterial protein synthesis although it does not itself have any significant antimicrobial by binding to the 30S ribosomal subunit, and retains activ- activity.51,59–61) ity against Enterobacteriaceae and A. baumannii expressing tetracycline-specific resistance.45) Furthermore, it is unaffected 4. Novel β-Lactams for MDR Gram-negative Bacteria by transferable resistance mechanisms such as KPC, metallo Cefiderocol (S-649266) (Fig. 3) is a novel siderophore β-lactamase (MBL), OXA, and RNA methylase.46) cephalosporin62,63) developed by Shionogi & Co., Ltd., that demonstrates notable activity against all the critical bacteria 3. Novel Polymyxin-class Antibiotics for MDR Gram- indicated by WHO, including carbapenem-resistant A. bau- negative Bacteria mannii, carbapenem-resistant P. aeruginosa, and CRE includ- Polymyxins are cationic lipopeptides and represent a last ing ESBL, KPC, and NDM-1.64–73) Furthermore, cefiderocol resort for the treatment of serious MDR Gram-negative bac- exhibits broad-spectrum activity against other ESKAPE teria.47) However, their clinical use is limited by their high pathogens.72,74,75) The chemical structure of cefiderocol was nephrotoxicity and neurotoxicity. SPR206 and SPR741 (Fig. rationally designed to penetrate the outer cell membrane 2) are novel polymyxin-B derivatives developed by Spero of Gram-negative bacteria and overcome resistance mecha- Therapeutics. SPR206 exhibits potency against all ESKAPE nisms.76) Efficient penetration of cefiderocol is performed by (Klebsiella pneumoniae, A. baumannii, P. aeruginosa, or trapping a ferric ion with the catechol moiety as a siderophore, Enterobacter species) pathogens,48) including serine-CRE, then the agent is actively transported into bacterial cells by a metallo-CRE, carbapenem-resistant P. aeruginosa, and A. Trojan horse strategy.77) Consequently, the agent is retained in baumannii.49,50) SPR206 interacts with lipopolysaccharides to high concentrations in the periplasmic space, where it inhibits 184 Chem. Pharm. Bull. Vol. 68, No. 3 (2020)

Fig. 3. Structures of Cefiderocol, BOS-228, and Associated Monobactam Antibiotics cell wall synthesis. In addition to its broad range of antimicro- β-lactamase inhibitors.105) bial activity, the stability of cefiderocol against β-lactamases, ETX0282CPDP is the first oral β-lactam/β-lactamase inhib- including ESBL, KPC, and NDM-1, has been confirmed.78–80) itor combination drug consisting of cefpodoxime proxetil (oral Cefiderocol has been evaluated in phase III clinical trials81) cephalosporin) and ETX0282 (an oral prodrug of diazabicy- and was submitted in a New Drug Application to the FDA in clooctane-class β-lactamase inhibitor) (Fig. 4). ETX0282CPDP December 2018 and in a Marketing Authorization Application was developed by Entasis Therapeutics, Inc., and is being to the European Medicines Agency in March 2019. evaluated in phase I clinical trials for the treatment of infec- BOS-228 (LYS228) (Fig. 3) is a potentially best-in-class tions caused by MDR Enterobacteriaceae, including CRE.106) monobactam developed by Boston Pharmaceuticals (Licensed Conversion of the ester moiety of ETX0282 in vivo pro- from Novartis AG). It is now being evaluated in phase II clini- duces ETX1317 (Fig. 4), which inhibits Ambler class A and cal trials with QIDP status for the treatment of complicated C enzymes and select class D enzymes.107) Cefpodoxime urinary tract infections (cUTIs)82) and cIAIs.83) Monobactams proxetil,108) a third-generation semi-synthetic cephalosporin, are intrinsically stable to MBL.84) However, aztreonam (Fig. is transformed to cefpodoxime (Fig. 4) as the active agent. 3), a first-generation monobactam, is degraded by serine In preclinical studies, ETX0282 restored the antimicrobial β-lactamase (SBL), which is often co-expressed with MBL activity of cefpodoxime against Enterobacteriaceae that had in clinically relevant Enterobacteriaceae.85) BOS-228 was de- acquired resistance to fluoroquinolones, cephalosporins, and signed to exhibit stability against MBL and SBL. Its structural carbapenems.107,109,110) design concept was derived from the fact that carumonam and Imipenem/Cilastatin/Relebactam (MK-7655A). MK- BO-1158, which possess a 4-cis configured β-lactam ring, are 7655A consists of three components: imipenem (carbapenem), more stable to SBL than aztreonam.86) Based on this fact, a cilastatin (renal DHP inhibitor), and relebactam (a novel SAR study of 4-cis configured β-lactams was conducted.87,88) β-lactamase inhibitor) (Fig. 4). It was developed by Merck The introduction of oxazolidinone to the side branch of the & Co., Inc., and is being evaluated in phase III clinical trials monobactam, and cyclopropanation on the carboxylic acid with QIDP status and Fast Track designation.111,112) A combi- moiety, increased its stability against SBL and MBL89) and in- nation of imipenem and cilastatin had been sold since 1987 creased its antimicrobial activity for NDM-1, KPC, and most under the brand name Primaxin.113) Relebactam, a diazabicy- ESBL.90–92) BOS-228 inhibits the growth of Escherichia coli clooctane-class β-lactamase inhibitor containing a piperidine by binding to penicillin-binding protein 3, a mechanism simi- moiety, inhibits class A and class C β-lactamases114,115) and lar to that of aztreonam.93) also restores the antimicrobial activity of imipenem against clinically relevant imipenem-resistant P. aeruginosa and K. 5. Novel β-Lactam/β-Lactamase Inhibitors for MDR pneumoniae.116–119) A SAR study of relebactam revealed that Gram-negative Bacteria replacement of the piperidine with a pyrrolidine or azepane The combination of a β-lactam and a β-lactamase inhibi- ring resulted in comparable β-lactamase inhibition activity tor is a well-established method for retaining the activity of and a synergistic effect with imipenem, whereas methylation β-lactam by suppressing the enzymatic hydrolysis of its of the amide moiety decreased the inhibition of KPC-2 and β-lactam ring.94,95) However, several bacteria have already AmpC.120,121) FDA has accepted MK-7655A for review as a acquired resistance to β-lactam/β-lactamase inhibitor combi- new drug application in the treatment of cUTIs122) and cIAIs nations. Recently, vaborbactam,96–98) a first-in-class boronic caused by certain susceptible Gram-negative bacteria. acid β-lactamase inhibitor that inhibits KPC-producing En- Nacubactam/Meropenem (OP0595/RG6080). Nacubactam terobacteriaceae, was introduced to clinical practice. Vabor- (NAC, RG6080, OP0595)123–126) (Fig. 4) is a novel diazabicy- bactam/meropenem (Vabomere™) (Fig. 4) was approved for clooctane-class β-lactamase inhibitor developed by NacuGen the treatment of cUTIs.99–104) The current clinical pipeline Therapeutics, Inc. (a joint venture of Meiji Seika Pharma Co., mainly contains structurally modified diazabicyclooctane-type Ltd./Fedora Pharmaceuticals, Inc.). Nacubactam has received Vol. 68, No. 3 (2020) Chem. Pharm. Bull. 185

Fig. 4. Structures of Novel β-Lactamase Inhibitors and Associated Antibiotics

Fast Track and QIDP designations by the FDA, and is cur- 2-methoxy-3-methylbenzoic acid in 11 steps via stereoselective rently being evaluated in phase I clinical trials. Nacubactam one-carbon homologation.137) Cefepime/VNRX-5133 exhibits inactivates class A and class C β-lactamases, and exhibits potency against β-lactamase—producing Enterobacteriaceae antibacterial activity against Enterobacteriaceae by binding and P. aeruginosa, including strains resistant to ceftazidime/ to penicillin-binding protein 2.127) Furthermore, nacubactam avibactam, ceftolozane/tazobactam,138) and cefepime, me- enhances the activity of partnered β-lactams that bind to ropenem, and piperacillin/tazobactam non-susceptible iso- other penicillin-binding proteins.128) In non-clinical studies, lates.139,140) Furthermore, VNRX-5133 restores the antimicrobi- the combination of nacubactam and meropenem129) (Fig. 4), al activity of cefepime in the presence of NDM-1—producing a carbapenem antibiotic, was shown to have potent antimi- Enterobacteriaceae.141) VNRX-5133 has QIDP status and Fast crobial activity against cUTIs and severe respiratory tract Track designation for the treatment of cUTIs and cIAIs. infections caused by meropenem-resistant Enterobacteriaceae WCK 5222 is a combination of cefepime and the novel and CRE.130,131) Nacubactam/meropenem exhibits much better β-lactam enhancer zidebactam (Fig. 4) that has been de- activity than that of piperacillin/tazobactam,123,132) as well as veloped by Wockhardt Ltd. It is being evaluated in phase I potent activity against carbapenem-resistant K. pneumoniae clinical trials with QIDP status.142,143) Zidebactam, a diazabi- via a different mechanism from that of avibactam.133) cyclooctane-class non-β-lactam antibiotic bearing a hydrazide Cefepime/VNRX-5133 (Taniborbactam) (Fig. 4) is a com- moiety, exhibits a dual mechanism of action and high afﬁn- bination of the fourth-generation cephalosporin cefepime134) ity for binding to penicillin-binding protein 2, resulting in and the next-generation β-lactamase inhibitor developed by the inhibition of Ambler class A and C β-lactamases.144–147) VenatoRx Pharmaceuticals Inc. Its phase III trials in patients Zidebactam also acts as a β-lactam enhancer when combined with cUTIs were initiated in August 2019. VNRX-5133, with cephalosporin.148) While cefepime has antimicrobial ac- an injectable β-lactamase inhibitor containing a bicyclic tivity against A. baumannii,149) cefepime/zidebactam exhibits boronate moiety, exhibits direct inhibitory activity against better antimicrobial activity against A. baumannii in vitro Ambler class A (ESBL, KPC), class B (NDM, VIM), class and in vivo than cefepime alone.144,150,151) Accordingly, WCK C (AmpC), and class D β-lactamases, and also enhances the 5222 shows potency for Enterobacteriaceae and P. aeruginosa activity of cefepime against CRE and carbapenem-resistant producing clinically relevant β-lactamases, including ESBL, P. aeruginosa.135,136) VNRX-5133 was synthesized from KPC, AmpC, and MBL.147,152–155) 186 Chem. Pharm. Bull. Vol. 68, No. 3 (2020)

Fig. 5. Structures of TS3112 and Apramycin

Cefepime/Enmetazobactam (Formerly AAI101) (Fig. 4) is a combination of cefepime and a novel β-lactamase inhibitor developed by Allecra that has entered phase III clinical trials for the treatment of cUTIs with QIDP status and Fast Track designation. Enmetazobactam is a novel penicillanic acid sulfone ESBL inhibitor that exhibits potent antimicrobial activity for Gram-negative pathogens, and restores the activity of cefepime against class A (ESBL).156,157) Enmetazobactam was designed to increase the cell wall penetration ability of tazobactam for Gram-negative bacteria. The methylation of tazobactam’s triazole moiety yielded enmetazobactam as a zwitterion that exhibits high permeability of the bacterial cell wall. Cefepime is also a zwitterion.158) Enmetazobactam’s mechanism of β-lactamase inhibition differs from that of tazo- 159) bactam. Cefepime is stable in the presence of AmpC and Fig. 6. Structure of Murepavadin OXA-48. Cefepime/enmetazobactam outperforms piperacillin/ tazobactam, and is as potent as meropenem toward Entero- bacteriaceae and the subset of ESBL-producing E. coli and K. 7. Novel Antibiotics for MDR Gram-negative Bacteria pneumoniae isolates.159–164) Murepavadin (Formerly POL7080) (Fig. 6) is a novel AIC499/Unknown β-Lactamase Inhibitor. AIC499 is a antibiotic with a new mechanism of action,171) developed by novel β-lactam developed by AiCuris. It is currently being Polyphor AG. It is being evaluated in phase III clinical tri- evaluated in phase I clinical trials. The combination of als with QIDP status for the treatment of hospital-acquired AIC499 and an unknown β-lactamase inhibitor shows potent bacterial pneumonia and ventilator-associated bacterial pneu- antimicrobial activity against MDR strains of P. aeruginosa, monia.172,173) Murepavadin is a peptide mimetic antibiotic A. baumannii, and β-lactamases such as Ambler class A, class comprising a cyclic peptide structure with 16 amino acids. It B, class C, and some class D enzymes.165,166) However, lim- was synthesized with reference to the structure of protegrin I. ited information on this system is currently available, and the Murepavadin selectively works against P. aeruginosa, whereas structure of AIC499 is not currently disclosed. it is inactive against most other Gram-negative and -positive bacteria. Murepavadin has a novel mechanism that targets the 6. Novel Aminoglycosides for MDR Gram-negative outer membrane proteins of bacteria, namely the lipopolysac- Bacteria charide transport protein D.174,175)In vitro antimicrobial evalu- There are currently no aminoglycoside antibiotics that exhibit ation has demonstrated that murepavadin is effective against efficacy in the treatment of infections caused by NDM-1— MDR and highly drug-resistant P. aeruginosa, including producing CRE and/or 16S ribosomal RNA methyltransferase- carbapenem-resistant and colistin-resistant organisms. Fur- producing bacteria. TS3112 (Fig. 5), a semi-synthetic amino- thermore, it exhibits 4- to 8-fold more potent antibacterial glycoside derived from apramycin,167) was developed by the activity than colistin and polymyxin-B.176,177) Because of Institute of Microbial Chemistry (BIKAKEN) and Meiji Seika murepavadin’s novel mode of action, cross-resistance with Pharma Co., Ltd.168,169) Chemical modification of apramycin other antibiotics is unlikely to occur.178) Furthermore, the P. led to TS3112 via stereo-inversion of the hydroxyl group at aeruginosa-specific action of murepavadin is likely to prevent C-5 and attachment of an (S)-3-amino-2-hydroxypropionic the diffusion of resistance to other pathogenic bacteria. acid to the amino group at C-4.” TS3112 is the first aminoglycoside antibiotic to exhibit potency against NDM-1—pro- 8. Conclusion ducing CRE and 16S ribosomal RNA methyltransferase- In this review, we have discussed promising antibiotics ac- producing bacteria. Furthermore, TS3112 possesses a unique tive against highly dangerous MDR Gram-negative bacteria, antibacterial profile, being effective against P. aeruginosa and particularly those effective against CRE, MDR P. aeruginosa, A. baumannii, as well as against Gram-positive bacteria in- and MDR A. baumannii. Our survey of these promising anti- cluding Methicillin-resistant Staphylococcus aureus.170) Hence, biotics revealed that natural product chemistry and synthetic TS3112 is expected to evolve into a key next-generation drug organic chemistry still play key roles in the discovery and de- for the treatment of severe infections caused by MDR Gram- velopment of antibiotics. Innovative fluorocyclines have been negative bacteria that are difficult to treat with existing drugs. developed by a synthetic chemical approach and by the SAR study of fully synthetic tetracycline scaffolds. Novel β-lactam Vol. 68, No. 3 (2020) Chem. Pharm. Bull. 187 antibiotics have been produced by chemical modification and Commun., 7, 1694–1715 (2016). the incorporation of functional units to the β-lactam skeleton. 20) Lakemeyer M., Zhao W., Mandl F. A., Hammann P., Sieber S. A., Simple strategic chemical transformation of the diazabicy- Angew. Chem. Int. Ed., 57, 14440–14475 (2018). 21) Liu F., Myers A. G., Curr. Opin. Chem. Biol., 32, 48–57 (2016). clooctane framework has yielded several novel β-lactamase 22) Wright P. M., Seiple I. B., Myers A. G., Angew. Chem. Int. Ed., 53, inhibitors, whereas the development of next-generation poly- 8840–8869 (2014). myxins and aminoglycosides have been achieved by a semi- 23) Clark R. B., Hunt D. K., He M., Achorn C., Chen C.-L., Deng Y., synthetic method based on natural products. A synthetic bio- Fyfe C., Grossman T. H., Hogan P. C., O’Brien W. J., Plamondon mimetic approach to a protegrin 1 mimic led to the discovery L., Rönn M., Sutcliffe J. A., Zhu Z., Xiao X.-Y., J. Med. 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