Strategic Approaches to Overcome Resistance against Gram-Negative Pathogens Using β-Lactamase Inhibitors and β-Lactam Enhancers: Activity of Three Novel Diazabicyclooctanes WCK 5153, Zidebactam (WCK 5107), and WCK 4234

Papp-Wallace, Krisztina M.; Nguyen, Nhu; Jacobs, Michael; Bethel, Christopher R.; Barnes, Melissa D.; Kumar, Vijay; Bajaksouzian, Saralee; Rudin, Susan D.; Rather, Philip N.; Bhavsar, Satish; Tadiparthi, Ravikumar; Deshpande, P. K.; Patil, V. J.; Yeole, Ravindra; Bhagwat, Sachin; Patel, Mahesh; Akker, F. van den; Bonomo, Robert A.

doi:10.1021/acs.jmedchem.8b00091

Cited by 126 publications

(151 citation statements)

References 39 publications

(110 reference statements)

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“…It was obtained from nitrile 58, which stemmed from primary amide 7 by trifluoroacetic anhydride-mediated dehydration (74% yield). 52 The latter was demonstrated to be particularly promising as it could not only inhibit SBLs of classes A and C but also oxacillinases of class D, including carbapenemases such as OXA-48. 52…”

Section: Zidebactam and Congenersmentioning

confidence: 99%

Synthetic approaches towards avibactam and other diazabicyclooctane β-lactamase inhibitors

Peilleron

Cariou

2020

Org. Biomol. Chem.

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Section: Zidebactam and Congenersmentioning

confidence: 99%

Synthetic approaches towards avibactam and other diazabicyclooctane β-lactamase inhibitors

Peilleron

Cariou

2020

Org. Biomol. Chem.

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“…142,143) Zidebactam, a diazabicyclooctane-class non-β-lactam antibiotic bearing a hydrazide moiety, exhibits a dual mechanism of action and high affinity for binding to penicillin-binding protein 2, resulting in the inhibition of Ambler class A and C β-lactamases. [144][145][146][147] Zidebactam also acts as a β-lactam enhancer when combined with cephalosporin. 148) While cefepime has antimicrobial activity against A. baumannii, 149) cefepime/zidebactam exhibits better antimicrobial activity against A. baumannii in vitro and in vivo than cefepime alone.…”

Section: Novel β-Lactam/β-lactamase Inhibitors For Mdr Gram-negative mentioning

confidence: 99%

“…144,150,151) Accordingly, WCK 5222 shows potency for Enterobacteriaceae and P. aeruginosa producing clinically relevant β-lactamases, including ESBL, KPC, AmpC, and MBL. 147,[152][153][154][155] 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.…”

Section: Novel β-Lactam/β-lactamase Inhibitors For Mdr Gram-negative mentioning

confidence: 99%

Potent Antibiotics Active against Multidrug-Resistant Gram-Negative Bacteria

Otsuka

2020

Chem. Pharm. Bull.

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The emergence of multidrug-resistant (MDR) Gram-negative bacteria has become a global problem. Among MDR Gram-negative bacteria, carbapenem-resistant Enterobacteriaceae (CRE), MDR Pseudomonas 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/βlactamase 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 2. Novel Tetracycline-class Antibiotics for MDR Gramnegative Bacteria Tetracycline antibiotics derived from natural products do not contain substituents at the C-7, C-8, and C-9 positions. However, the development of totally synthetic methods to synthesize tetracyclines has made it possible to modify these three positions, 21,22) providing novel and fully synthetic tetracyclines such as XERAVA and TP-6076, developed by Tetraphase Pharmaceuticals Inc. (Fig. 1). The introduction of an electron-withdrawing group at the C-7 position, and substitution at the C-9 position, significantly improved the antimicrobial activity of these synthetic tetracyclines. 23,24) XERAVA (eravacycline, TP-434) 25-27) was the first fully synthetic fluorocycline produced by Michael-Dieckmann reaction. 28) XERAVA was approved by the U.S. Food and Drug Administration (FDA) in August 27, 2018 for the treatment of

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“…This inhibitors include avibactam and relebactam, the agents forming carbamyl-enzyme complexes with the catalytic serine residue, which further undergo slow, reversible recyclization with an inhibitor molecule being released [70,71]. These inhibitors exhibit activity against βLs of classes A, C, and, partially, against class D [72,73]. However, microorganisms also develop resistance to these inhibitors [74,75].…”

Section: Current Approaches For Overcoming the Resistance Conferred Bmentioning

confidence: 99%

The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases

et al. 2019

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Bacterial resistance to β-lactams, the most commonly used class of antibiotics, poses a global challenge. This resistance is caused by the production of bacterial enzymes that are termed β-lactamases (βLs). The evolution of serine-class A β-lactamases from penicillin-binding proteins (PBPs) is related to the formation of the Ω-loop at the entrance to the enzyme's active site. In this loop, the Glu166 residue plays a key role in the two-step catalytic cycle of hydrolysis. This residue in TEM-type β-lactamases, together with Asn170, is involved in the formation of a hydrogen bonding network with a water molecule, leading to the deacylation of the acyl-enzyme complex and the hydrolysis of the β-lactam ring of the antibiotic. The activity exhibited by the Ω-loop is attributed to the positioning of its N-terminal residues near the catalytically important residues of the active site. The structure of the Ω-loop of TEM-type β-lactamases is characterized by low mutability, a stable topology, and structural flexibility. All of the revealed features of the Ω-loop, as well as the mechanisms related to its involvement in catalysis, make it a potential target for novel allosteric inhibitors of β-lactamases.Biomolecules 2019, 9, 854 2 of 16 of inhibitors, whose structures are based on the β-lactam ring, is also limited because resistance to them has also developed. Today, a promising trend is to design novel βL inhibitors and simultaneously use them with antibiotics [7,8]. Computer methods involving the in silico search of novel inhibitors has significantly broadened the range of potential inhibitors. However, only a limited number of novel βL inhibitors have been found that are of non-β-lactam nature and are capable of binding close to the enzyme's active site [8][9][10][11]. Because of the relatively low inhibition constants of such inhibitors, this area of research needs to be further developed.Recently, special attention has been paid to studying the role of loops and peptide linkers as flexible elements in the functioning of proteins and enzymes [12,13]. The loops, as secondary structural elements of proteins, are characterized by an enhanced mobility; their role is not solely confined to being connecting units [12]. Furthermore, changes in the amino acid composition of the loops may impart new functions to protein superfamilies. The Ω-loops, a special class of loops with a conformation resembling the Greek letter "omega," are currently attracting specific attention. The loop conformation is ensured by the short-distance fixation of terminal amino acids. Ω-Loops have been observed in 60 proteins [13], some of which have been found to be involved in allosteric regulation during biospecific ligand recognition [14,15]. The structure of serine class A βLs represents a compact, conserved scaffold that consists of secondary structural elements linked by flexible loops. The Ω-loop is located at the bottom of the entrance to the enzyme active site and includes the catalytically important and highly conserved residue Glu166, the m...

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Strategic Approaches to Overcome Resistance against Gram-Negative Pathogens Using β-Lactamase Inhibitors and β-Lactam Enhancers: Activity of Three Novel Diazabicyclooctanes WCK 5153, Zidebactam (WCK 5107), and WCK 4234

Cited by 126 publications

References 39 publications

Synthetic approaches towards avibactam and other diazabicyclooctane β-lactamase inhibitors

Synthetic approaches towards avibactam and other diazabicyclooctane β-lactamase inhibitors

Potent Antibiotics Active against Multidrug-Resistant Gram-Negative Bacteria

The Role of the Ω-Loop in Regulation of the Catalytic Activity of TEM-Type β-Lactamases

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