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 e-mail: [email protected] © 2020 The Pharmaceutical Society of Japan Vol. 68, No. 3 (2020) Chem. Pharm. Bull. 183 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

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