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

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 AR-related 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.

SUBMITTER: Ayipo YO

PROVIDER: S-EPMC10285742 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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

Ayipo Yusuf Oloruntoyin YO Chong Chien Fung CF Mordi Mohd Nizam MN

RSC medicinal chemistry 20230331 6

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 <i>Enterobacteriaceae</i> 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 f ...[more]

PMID: 37360393

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Project description:BackgroundNDM-1 is a novel broad-spectrum metallo-β-lactamase with the capability to grant resistance to almost all β-lactam antibiotics. Its widespread dissemination made treatment options a major challenge to combat, causing threat to public health worldwide. Due to antibiotic resistance problems, development of effective therapeutics for infections caused by NDM-1 producing strains is urgently required. Since combination therapies are proved to be effective in many cases, this study was initiated to put forward novel effective antibiotics combinations for fighting infections caused by NDM-1 producing strains.MethodsStreptomycin and amikacin combination and streptomycin and ciprofloxacin combination were tested by checkerboard assay. NDM-1 protein/enzyme was then expressed and purified to carry out enzyme kinetics study, CD and fluorescence spectroscopic studies.ResultsStreptomycin and amikacin combination and streptomycin and ciprofloxacin combination showed synergistic effect towards NDM-1 producing bacterial strains as shown by FICI results. NDM-1 producing bacterial cells were expressed and purified to obtain protein as the source of enzyme. When NDM-1 enzyme was treated with streptomycin along with amikacin, the efficiency of enzyme was decreased by 49.37% and when the enzyme was treated with streptomycin along with ciprofloxacin, the efficiency of enzyme was decreased by 29.66% as revealed by enzyme kinetic studies. Due to binding of streptomycin and amikacin in combination and streptomycin and ciprofloxacin in combination, conformational changes in the secondary structure of NDM-1 enzyme were observed by CD spectroscopic studies. Antibiotics streptomycin and ciprofloxacin bind with NDM-1 through exothermic processes, whereas amikacin binds through an endothermic process. All three antibiotics bind spontaneously with an association constant of the order of 104 M-1 as revealed by fluorescence spectroscopic studies.ConclusionsThe therapeutic combination of streptomycin with amikacin and ciprofloxacin plays an important role in inhibiting NDM-1 producing bacterial strains. Therefore, these combinations can be used as effective future therapeutic candidates against NDM-1 producing bacterial cells.

Dataset Information

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

Publications

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

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