Small-molecule inhibitors of bacterial-producing metallo-β-lactamases: insights into their resistance mechanisms and biochemical analyses of their activities
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Date
2023-03-31
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Abstract
Antibiotic resistance (AR) remains one of the major threats to the global healthcare system, which is
associated with alarming morbidity and mortality rates. The defence mechanisms of Enterobacteriaceae to
antibiotics occur through several pathways including the production of metallo-β-lactamases (MBLs). The
carbapenemases, notably, New Delhi MBL (NDM), imipenemase (IMP), and Verona integron-encoded MBL
(VIM), represent the critical MBLs implicated in AR pathogenesis and are responsible for the worst ARrelated
clinical conditions, but there are no approved inhibitors to date, which needs to be urgently
addressed. Presently, the available antibiotics including the most active β-lactam-types are subjected to
deactivation and degradation by the notorious superbug-produced enzymes. Progressively, scientists have
devoted their efforts to curbing this global menace, and consequently a systematic overview on this topic
can aid the timely development of effective therapeutics. In this review, diagnostic strategies for MBL
strains and biochemical analyses of potent small-molecule inhibitors from experimental reports (2020-
date) are overviewed. Notably, N1 and N2 from natural sources, S3–S7, S9 and S10 and S13–S16 from
synthetic routes displayed the most potent broad-spectrum inhibition with ideal safety profiles. Their
mechanisms of action include metal sequestration from and multi-dimensional binding to the MBL active
pockets. Presently, some β-lactamase (BL)/MBL inhibitors have reached the clinical trial stage. This synopsis
represents a model for future translational studies towards the discovery of effective therapeutics to
overcome the challenges of AR.