6lhe
Crystal Structure of Gold-bound NDM-1
Structural highlights
FunctionBLAN1_KLEPN Confers resistance to many beta-lactam antibiotics, including some carbapenems. Does not confer resistance to the polymixin colistin or the fluoroquinolone ciprofloxacin. Publication Abstract from PubMedGlobal emergence of Gram-negative bacteria carrying the plasmid-borne resistance genes, blaMBL and mcr, raises a significant challenge to the treatment of life-threatening infections by the antibiotics, carbapenem and colistin (COL). Here, we identify an antirheumatic drug, auranofin (AUR) as a dual inhibitor of metallo-beta-lactamases (MBLs) and mobilized colistin resistance (MCRs), two resistance enzymes that have distinct structures and substrates. We demonstrate that AUR irreversibly abrogates both enzyme activity via the displacement of Zn(II) cofactors from their active sites. We further show that AUR synergizes with antibiotics on killing a broad spectrum of carbapenem and/or COL resistant bacterial strains, and slows down the development of beta-lactam and COL resistance. Combination of AUR and COL rescues all mice infected by Escherichia coli co-expressing MCR-1 and New Delhi metallo-beta-lactamase 5 (NDM-5). Our findings provide potential therapeutic strategy to combine AUR with antibiotics for combating superbugs co-producing MBLs and MCRs. Resensitizing carbapenem- and colistin-resistant bacteria to antibiotics using auranofin.,Sun H, Zhang Q, Wang R, Wang H, Wong YT, Wang M, Hao Q, Yan A, Kao RY, Ho PL, Li H Nat Commun. 2020 Oct 16;11(1):5263. doi: 10.1038/s41467-020-18939-y. PMID:33067430[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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