Computational and biological profile of boronic acids for the detection of bacterial serine- and metallo-β-lactamases

AmpC beta-lactamases; Enterobacteriaceae infection; Anti-Bacterial Agents; Bacteria; Bacterial Proteins; Boronic Acids; Cefotaxime; Ceftazidime; Computational Biology; Drug Resistance, Bacterial; Enterobacteriaceae Infections; Microbial Sensitivity Tests

Abstract :

[en] 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 (K i = 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. © 2017 The Author(s).

Disciplines :

Biochemistry, biophysics & molecular biology
Life sciences: Multidisciplinary, general & others
Microbiology

Author, co-author :

Santucci, M.; Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, Modena, 41125, Italy

Spyrakis, F.; Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, Modena, 41125, Italy, Department of Drug Science and Technology, University of Turin, Via Pietro Giuria 9, Turin, 10125, Italy

Cross, S.; Molecular Discovery Limited, 215 Marsh Road, Pinner Middlesex, London, HA5-5NE, United Kingdom

Quotadamo, A.; Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, Modena, 41125, Italy

Farina, D.; Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, Modena, 41125, Italy

Tondi, D.; Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, Modena, 41125, Italy

De Luca, F.; Dipartimento di Biotecnologie Mediche, University of Siena, Viale Bracci 16, Siena, 53100, Italy

Docquier, Jean-Denis ; Université de Liège - ULiège > Département des sciences de la vie > Centre d'ingénierie des protéines

Prieto, A. I.; Biomedicine Institute of Sevilla (IBIS), CSIC, Avda. Manuel Siurot, sn., Sevilla, Spain

Ibacache, C.; National Center of Biotechnology, CSIC, Calle Darwin, 3, Madrid, 28049, Spain

More authors (4 more)

Language :

English

Title :

Computational and biological profile of boronic acids for the detection of bacterial serine- and metallo-β-lactamases

Publication date :

2017

Journal title :

Scientific Reports

eISSN :

2045-2322

Publisher :

Nature Publishing Group

Volume :

Issue :

Peer reviewed :

Peer Reviewed verified by ORBi

Funders :

European Regional Development Fund, FEDERRD12/0015/0012Ministerio de EconomÃa y Competitividad, MINECOEuropean Regional Development Fund, FEDERGM63815Instituto de Salud Carlos III, ISCIII

Available on ORBi :

since 19 November 2020

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