Potent Antibiotics Active against Multidrug-Resistant Gram-Negative Bacteria

Abstract

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

Antimicrobial Peptides and Cationic Nanoparticles: A Broad-Spectrum Weapon to Fight Multi-Drug Resistance Not Only in Bacteria

“…Although many novel molecules with antimicrobial activity have been synthesized, only a few are undergoing clinical trials and are active against MDR pathogens [ 16 ]. For this reason, research has focused on finding other alternative strategies.…”

Polymyxins and Bacterial Membranes: A Review of Antibacterial Activity and Mechanisms of Resistance

“…Given their distinctive cellular features, Gram-negative bacteria are said to specifically develop and acquire dynamic resistance patterns and cause significant morbidity and mortality worldwide. Among these, carbapenem-resistant Enterobacteriaceae , MDR Pseudomonas aeruginosa , and MDR Acinetobacter baumannii represent serious pressures to antimicrobial therapy, due to the extremely limited efficacious treatment options [ 2 ]. Against such pathogens, polymyxins represent one of the last-resort antibiotics that is still effective [ 3 ], among few others, including fosfomycin, ceftazidime/avibactam and the recently approved meropenem–vaborbactam [ 4 , 5 ].…”

Ab initio Designed Antimicrobial Peptides Against Gram-Negative Bacteria

“…Gram-negative bacteria contain an outer membrane that protects the bacterium from environmental toxins and provides efflux out of the cell ( Silhavy et al, 2010 ). This membrane permeability barrier has historically restricted the discovery of narrow-spectrum antibiotics against Gram-negative bacteria and this challenge is further compounded due to the rise in multi-drug resistance (MDR) strains resistant to multiple classes of antibiotics ( Liu et al, 2019 ; Otsuka, 2020 ). Finally, Gram-negative bacteria can also use biofilms (a virulence factor) as a means to confer phenotypic antibiotic resistance which can make the bacteria up to 1,000-fold times more resistant when embedded in the exopolysaccharide matrix ( Cepas et al, 2018 ).…”