6ts9
Crystal structure of GES-5 carbapenemaseCrystal structure of GES-5 carbapenemase
Structural highlights
FunctionBLAG5_KLEPN Confers resistance to penicillins, cephalosporins and carbapenems (PubMed:20696873, PubMed:27590339). Has carbapenem-hydrolyzing activity (PubMed:27590339).[1] [2] Publication Abstract from PubMedThe worldwide spread of beta-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. Targeting the Class A Carbapenemase GES-5 via Virtual Screening.,Klein R, Cendron L, Montanari M, Bellio P, Celenza G, Maso L, Tondi D, Brenk R Biomolecules. 2020 Feb 14;10(2). pii: biom10020304. doi: 10.3390/biom10020304. PMID:32075131[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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