Abstract
β-Lactamases (BLs) able to hydrolyze β-lactam antibiotics and more importantly the last resort carbapenems, represent a major mechanism of resistance in Gram-negative bacteria showing multi-drug or extensively drug resistant phenotypes. The early detection of BLs responsible of resistant infections is challenging: approaches aiming at the identification of new BLs inhibitors (BLI) can thus serve as the basis for the development of highly needed diagnostic tools. Starting from benzo-[b]-thiophene-2-boronic acid (BZB), a nanomolar inhibitor of AmpC β-lactamase (Ki = 27 nM), we have identified and characterized a set of BZB analogues able to inhibit clinically-relevant β-lactamases, including AmpC, Extended-Spectrum BLs (ESBL), KPC- and OXA-type carbapenemases and metallo-β-lactamases (MBL). A multiligand set of boronic acid (BA) β-lactamase inhibitors was obtained using covalent molecular modeling, synthetic chemistry, enzyme kinetics and antibacterial susceptibility testing. Data confirmed the possibility to discriminate between clinically-relevant β-lactamases on the basis of their inhibition profile. Interestingly, this work also allowed the identification of potent KPC-2 and NDM-1 inhibitors able to potentiate the activity of cefotaxime (CTX) and ceftazidime (CAZ) against resistant clinical isolates (MIC reduction, 32-fold). Our results open the way to the potential use of our set of compounds as a diagnostic tool for the sensitive detection of clinically-relevant β-lactamases.
Highlights
Antibiotic resistance is a serious concern in hospital and community settings
The emergence, in particular, of KPC-type enzymes resistant to colistin[7,8,9], CTX-M type associated with resistance to quinolones and aminoglycosides[10] and with blaNDM-1-carrying plasmids[11], AmpC enzymes of which overproduction is coupled with other resistant mechanism[12] and VIM- and NDM-type associated with multiple resistance determinants on narrow and broad host-range plasmids[13] led to the diffusion of multi-drug resistant (MDR) pathogens, and the emergence of extensively drug or pan-drug resistant isolates, significantly narrowing the antibiotic treatment options[14,15]
From an integrated approach aiming at evaluating the interaction of a boronic acids set against a selected BLs panel including clinically-relevant AmpCs, ESBLs, serine and metallo-carbapenemases, we identified C5-substituted BZB derivatives
Summary
Antibiotic resistance is a serious concern in hospital and community settings. Production of β-lactamases (BLs) is a prevalent resistance mechanism in bacterial infections and a threat to the available antibiotic armamentarium[1,2,3]. Several new β-lactamase inhibitors entered clinical trials or received FDA-approval, including diazabicyclooctanes (avibactam, relebactam and nacubactam) and the boronic acid vaborbactam (RPX7009) The latter class of BL inhibitors covalently and reversibly inhibit serine-BLs and revert β-lactam resistance in BL-producing bacteria. The ability of single compounds in a multi-ligand set to inhibit specific BLs with different potencies would potentially allow to discriminate between various types of clinically-relevant BLs produced by a clinical isolate via the analysis of the resulting inhibition profile In this context, we report the characterization of a set of benzo[b]thiophene-2-boronic acid derivatives showing differentiated inhibition profiles towards clinically relevant BLs. Selected boronic acids were investigated for their potential application in phenotypic tests for the simple and sensitive detection of the production of various β-lactamases in clinical isolates[24,25]
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