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Targeting the Class A carbapenemase GES-5 via virtual screening

DOI: 10.3390/biom10020304 DOI Help

Authors: Raphael Klein (Johannes Gutenberg University) , Laura Cendron (University of Padova) , Martina Montanari (University of Modena and Reggio Emilia) , Pierangelo Bellio (University of L’Aquila) , Giuseppe Celenza (University of L’Aquila) , Lorenzo Maso (University of Padova) , Donatella Tondi (University of Modena and Reggio Emilia) , Ruth Brenk (University of Bergen)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Biomolecules , VOL 10

State: Published (Approved)
Published: February 2020
Diamond Proposal Number(s): 21741

Open Access Open Access

Abstract: The worldwide spread of β-lactamases able to hydrolyze last resort carbapenems contributes to the antibiotic resistance problem and menaces the successful antimicrobial treatment of clinically relevant pathogens. Class A carbapenemases include members of the KPC and GES families. While drugs against KPC-type carbapenemases have recently been approved, for GES-type enzymes, no inhibitors have yet been introduced in therapy. Thus, GES carbapenemases represent important drug targets. Here, we present an in silico screening against the most prevalent GES carbapenemase, GES-5, using a lead-like compound library of commercially available compounds. The most promising candidates were selected for in vitro validation in biochemical assays against recombinant GES-5 leading to four derivatives active as high micromolar competitive inhibitors. For the best inhibitors, the ability to inhibit KPC-2 was also evaluated. The discovered inhibitors constitute promising starting points for hit to lead optimization.

Journal Keywords: antibiotic resistance; GES-5; Guyana extended-spectrum-β-lactamase; carbapenemase; virtual screening; docking; noncovalent inhibition

Subject Areas: Biology and Bio-materials, Medicine


Instruments: I03-Macromolecular Crystallography

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