Recent Developments to Cope the Antibacterial Resistance via β-Lactamase Inhibition

Abstract

Antibacterial resistance towards the β-lactam (BL) drugs is now ubiquitous, and there is a major global health concern associated with the emergence of new β-lactamases (BLAs) as the primary cause of resistance. In addition to the development of new antibacterial drugs, β-lactamase inhibition is an alternative modality that can be implemented to tackle this resistance channel. This strategy has successfully revitalized the efficacy of a number of otherwise obsolete BLs since the discovery of the first β-lactamase inhibitor (BLI), clavulanic acid. Over the years, β-lactamase inhibition research has grown, leading to the introduction of new synthetic inhibitors, and a few are currently in clinical trials. Of note, the 1, 6-diazabicyclo [3,2,1]octan-7-one (DBO) scaffold gained the attention of researchers around the world, which finally culminated in the approval of two BLIs, avibactam and relebactam, which can successfully inhibit Ambler class A, C, and D β-lactamases. Boronic acids have shown promise in coping with Ambler class B β-lactamases in recent research, in addition to classes A, C, and D with the clinical use of vaborbactam. This review focuses on the further developments in the synthetic strategies using DBO as well as boronic acid derivatives. In addition, various other potential serine- and metallo- β-lactamases inhibitors that have been developed in last few years are discussed briefly as well. Furthermore, binding interactions of the representative inhibitors have been discussed based on the crystal structure data of inhibitor-enzyme complex, published in the literature.

Small-molecule inhibitors of bacterial-producing metallo-β-lactamases: insights into their resistance mechanisms and biochemical analyses of their activities

“…The first BLs, AmpC cephalosporinase (chromosomally encoded), were isolated from E. coli in the early 1940s. 4,46,47 As early BLs, they contributed to the development of resistance toward the first β-lactam antibiotic, penicillin. Two decades later, scientists discovered an E. coli-derived penicillinase called TEM-1, which is part of a novel category of transferable narrow-spectrum BL (NSBL).…”

“…When tested against NDM-1/VIM-1-producing K. pneumonia strains, the checkerboard assay revealed synergism with meropenem, with S15 and S16 obtaining FIC index values of 0.19 and 0.05, respectively. 94 The [1,2,4]triazole derivative, 3-(4-bromophenyl)-6,7dihydro-5H- [1,2,4]triazolo [3,4-b][1,3]thiazine (S32) synthesised by Yuan et al inhibited VIM-2, with an IC 50 value of 38.36 μM, but barely inhibited both VIM-1 and VIM-5, as indicated by its 23% and 33% enzyme inhibition at a concentration of 100 μM, respectively. Further selectivity analysis confirmed its selectivity against VIM-2 MBL.…”

“…Also, it has been attributed to increased patient mortality and morbidity, owing to the limited therapeutic options available against resistant microbes at present. [3][4][5][6] Recently, the Centers for Disease Control and Prevention (CDC) announced that in 2019, at least 44 000 AR-related deaths occurred, marking a 2-fold increase in the death count compared to that in 2013 of 23 000. 7 Consequently, if efforts are not promptly devoted to addressing this issue, bacterial pathogens may evolve into a much more dangerous form, resulting in approximately 10 million annually deaths by 2050.…”

“…10 The 'golden era' of antibiotics spanned from 1940 to 1960; however, it was short-lived due to the evolution of bacteria into multi-drug resistance (MDR) or "superbugs". 4 Natural resistance develops gradually over time as a consequence of genetic changes; however, antibiotic overuse and poor stewardship in medical prescription can also accelerate this unpleasant process. 3,11 Under antibiotic effects, susceptible bacterial strains are eliminated or inhibited, but antibiotic-resistant strains can prevail.…”

Electric Fields Are a Key Determinant of Carbapenemase Activity in Class A β-Lactamases

“…In Gram-negative bacteria such as Escherichia coli , resistance to β-lactams, the most commonly prescribed antibiotic class, arises primarily through antibiotic hydrolysis by β-lactamases. − In class A β-lactamases, hydrolysis follows a two-step mechanism (Figures a and S1). β-Lactam breakdown commences with a nucleophilic attack of a catalytic serine on the amide carbonyl, leading to the formation of a covalent acyl-enzyme complex (AE) via a tetrahedral intermediate.…”