β-Lactamases (BLs) are among the main responsible of the threatening spread of Gram- negative pathogens resistant to available antibiotics, including last resort carbapenems. [1-2] The rapid detection of resistant BLs responsible of bacterial infections represents a critical challenge for the choice of the most appropriate therapy. As a consequence approaches aiming at the identification of new antibacterial agents or at the identification of the organisms conferring resistance in bacterial infections are strictly connected. Phenyl-boronic acids have been identified as valuable compounds preventing beta-lactam antibiotics hydrolysis by BLs and therefore prolonging antibiotics antimicrobial action. Diagnostic applications of boronic acids were previously foreseen highlighting the limited efficacy of a single boronic compound in the BLs detection: to reliably characterize each BL in the cellular environment a panel of molecules is needed. [3-5] In the present work we propose the inhibitory activity characterization of a benzen-boronic acids set against a selected panel of therapeutically relevant Extended Spectrum Beta-Lactamases (ESBLs). A multi-ligand approach is applied to BLs detection representing an improvement in the reliable recognition of a specific target enzyme: it relies on the differential profile of a selected inhibitor’s set against each considered BL in a panel of ESBLs. The exploited strategy includes covalent molecular docking, screening, synthetic chemistry, enzyme inhibition kinetic and cellular studies on clinical isolates. The inhibitory profile of the benzene-boronic acids compounds set against resistant bacteria overexpressing serine- and metallo- ESBLs belonging to class A, B, C and D has been obtained. Among the developed boronic acids set, one compound was able to potentiate cefotaxime against KPC-2 carbapenemase with a MIC value reduction of 32 fold, presenting an interesting antibacterial activity against NDM-1 and VIM-2 overexpressing resistant bacteria as well (32-fold improvement). [6] The obtained results open the way to the potential use of our selected compounds set as diagnostic tool for timely BLs detection.

Multiligand approach to the identification of resistant strains overexpressing beta-lactamase / Costi, Maria Paola; Santucci, Matteo; Spyrakis, Francesca; Cross, Simon; Farina, Davide Salvatore Francesco; Tondi, Donatella; Quotadamo, Antonio; Docquier, Jean Denis; Croce, Filomena; Prieto, Ana Isabel; Ibacache, Claudia; Blázquez, Jesús; Venturelli, Alberto; Cruciani, Gabriele. - (2017). ((Intervento presentato al convegno ICAR 2017 - 2nd International Caparica Conference in Antibiotic Resistance tenutosi a Caparica - Portugal nel 12th – 15th June 2017.

Multiligand approach to the identification of resistant strains overexpressing beta-lactamase

COSTI, Maria Paola;SANTUCCI, MATTEO;SPYRAKIS, FRANCESCA;FARINA, Davide Salvatore Francesco;TONDI, Donatella;QUOTADAMO, ANTONIO;VENTURELLI, Alberto;
2017

Abstract

β-Lactamases (BLs) are among the main responsible of the threatening spread of Gram- negative pathogens resistant to available antibiotics, including last resort carbapenems. [1-2] The rapid detection of resistant BLs responsible of bacterial infections represents a critical challenge for the choice of the most appropriate therapy. As a consequence approaches aiming at the identification of new antibacterial agents or at the identification of the organisms conferring resistance in bacterial infections are strictly connected. Phenyl-boronic acids have been identified as valuable compounds preventing beta-lactam antibiotics hydrolysis by BLs and therefore prolonging antibiotics antimicrobial action. Diagnostic applications of boronic acids were previously foreseen highlighting the limited efficacy of a single boronic compound in the BLs detection: to reliably characterize each BL in the cellular environment a panel of molecules is needed. [3-5] In the present work we propose the inhibitory activity characterization of a benzen-boronic acids set against a selected panel of therapeutically relevant Extended Spectrum Beta-Lactamases (ESBLs). A multi-ligand approach is applied to BLs detection representing an improvement in the reliable recognition of a specific target enzyme: it relies on the differential profile of a selected inhibitor’s set against each considered BL in a panel of ESBLs. The exploited strategy includes covalent molecular docking, screening, synthetic chemistry, enzyme inhibition kinetic and cellular studies on clinical isolates. The inhibitory profile of the benzene-boronic acids compounds set against resistant bacteria overexpressing serine- and metallo- ESBLs belonging to class A, B, C and D has been obtained. Among the developed boronic acids set, one compound was able to potentiate cefotaxime against KPC-2 carbapenemase with a MIC value reduction of 32 fold, presenting an interesting antibacterial activity against NDM-1 and VIM-2 overexpressing resistant bacteria as well (32-fold improvement). [6] The obtained results open the way to the potential use of our selected compounds set as diagnostic tool for timely BLs detection.
giu-2017
ICAR 2017 - 2nd International Caparica Conference in Antibiotic Resistance
Caparica - Portugal
12th – 15th June 2017
Costi, Maria Paola; Santucci, Matteo; Spyrakis, Francesca; Cross, Simon; Farina, Davide Salvatore Francesco; Tondi, Donatella; Quotadamo, Antonio; Docquier, Jean Denis; Croce, Filomena; Prieto, Ana Isabel; Ibacache, Claudia; Blázquez, Jesús; Venturelli, Alberto; Cruciani, Gabriele
Multiligand approach to the identification of resistant strains overexpressing beta-lactamase / Costi, Maria Paola; Santucci, Matteo; Spyrakis, Francesca; Cross, Simon; Farina, Davide Salvatore Francesco; Tondi, Donatella; Quotadamo, Antonio; Docquier, Jean Denis; Croce, Filomena; Prieto, Ana Isabel; Ibacache, Claudia; Blázquez, Jesús; Venturelli, Alberto; Cruciani, Gabriele. - (2017). ((Intervento presentato al convegno ICAR 2017 - 2nd International Caparica Conference in Antibiotic Resistance tenutosi a Caparica - Portugal nel 12th – 15th June 2017.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11380/1140681
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