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Open AccessArticle

Targeting the Class A Carbapenemase GES-5 via Virtual Screening

1
Institute of Pharmacy and Biochemistry, Johannes Gutenberg University, 55122 Mainz, Germany
2
Department of Biology, University of Padua, Viale G. Colombo 3, 35121 Padua, Italy
3
Department of Life Sciences, University of Modena and Reggio Emilia, Via Campi 103, 41125 Modena, Italy
4
Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, via Vetoio 1, 67100 L’Aquila, Italy
5
Department of Biomedicine, University of Bergen, Jonas Lies Vei 91, 5020 Bergen, Norway
*
Authors to whom correspondence should be addressed.
Biomolecules 2020, 10(2), 304; https://doi.org/10.3390/biom10020304 (registering DOI)
Received: 14 January 2020 / Revised: 10 February 2020 / Accepted: 11 February 2020 / Published: 14 February 2020
(This article belongs to the Special Issue Beta-Lactamases: Sequence, Structure, Function, and Inhibition)
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. View Full-Text
Keywords: antibiotic resistance; GES-5; Guyana extended-spectrum-β-lactamase; carbapenemase; virtual screening; docking; noncovalent inhibition antibiotic resistance; GES-5; Guyana extended-spectrum-β-lactamase; carbapenemase; virtual screening; docking; noncovalent inhibition
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Klein, R.; Cendron, L.; Montanari, M.; Bellio, P.; Celenza, G.; Maso, L.; Tondi, D.; Brenk, R. Targeting the Class A Carbapenemase GES-5 via Virtual Screening. Biomolecules 2020, 10, 304.

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