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dc.contributor.authorHInchliffe, Philip
dc.contributor.authorTanner, Carol A.
dc.contributor.authorKrismanich, Anthony
dc.contributor.authorLabbé, Geneviève
dc.contributor.authorGoodfellow, Valerie J.
dc.contributor.authorMarrone, Laura
dc.contributor.authorDesoky, Ahmed
dc.contributor.authorCalvopiña, Karina
dc.contributor.authorWhittle, Emily E.
dc.contributor.authorZeng, Fanxing
dc.contributor.authorAvison, Mathew B.
dc.contributor.authorBols, Niels C.
dc.contributor.authorSiemann, Stefan
dc.contributor.authorSpencer, James
dc.contributor.authorDmitrienko, Gary I. 20:08:50 (GMT) 20:08:50 (GMT)
dc.descriptionThis document is the Accepted Manuscript version of a Published Work that appeared in final form in Biochemistry, copyright © American Chemical Society after peer review and technical editing by publisher. To access the final edited and published work see
dc.description.abstractThere are currently no clinically available inhibitors of metallo-β-lactamases (MBLs), enzymes which hydrolyze β-lactam antibiotics and confer resistance on Gram-negative bacteria. Here we present 6-phosphonomethylpyridine-2-carboxylates (PMPCs) as potent inhibitors of subclass B1 (IMP-1, VIM-2, NDM-1) and B3 (L1) MBLs. Inhibition followed a competitive, slow-binding model without an isomerization step (IC50 values 0.3 – 7.2 µM; Ki 0.03 – 1.5 µM). Minimum inhibitory concentration assays demonstrated potentiation of β-lactam (meropenem) activity against MBL-producing bacteria, including clinical isolates, at concentrations where eukaryotic cells remain viable. Crystal structures revealed unprecedented modes of inhibitor binding to B1 (IMP-1) and B3 (L1) MBLs. In IMP-1, binding does not replace the nucleophilic hydroxide and the PMPC carboxylate and pyridine nitrogen interact closely (2.3 and 2.7 Å, respectively) with the Zn2 ion of the binuclear metal site. The phosphonate group makes limited interactions, but is 2.6 Å from the nucleophilic hydroxide. Furthermore, the presence of a water molecule interacting with the PMPC phosphonate and pyridine N-C2 π-bond, as well as the nucleophilic hydroxide, suggests that the PMPC binds to the MBL active site as its hydrate. Binding is markedly different in L1, with the phosphonate displacing both Zn2, forming a monozinc enzyme, and the nucleophilic hydroxide, while also making multiple interactions with the protein main chain and Zn1. The carboxylate and pyridine nitrogen interact with Ser221/223, respectively (3 Å distance). The potency, low toxicity, cellular activity and amenability to further modification of PMPCs indicate these and similar phosphonate compounds can be further considered for future MBL inhibitor development.en
dc.description.sponsorshipThis work was supported by grants from the U.K. Medical Research Council and Canadian Institutes of Health Research (U.K.-Canada Team Grant G1100135 and FRN114046) to J.S. and G.I.D, Canadian Institutes of Health Research operating grant (FRN106531) to G.I.D., the National Institute of Allergy and Infectious Diseases of the U.S. National Institutes of Health to J.S. (R01AI100560) and the Engineering and Physical Sciences Research Council (EP/M027546/1) to M.B.A. and J.S..K.C. was in receipt of a postgraduate scholarship from SENESCYT, Ecuador.en
dc.publisherAmerican Chemical Societyen
dc.titleStructural and Kinetic Studies on the Potent Inhibition of Metallo-β-Lactamases by 6- Phosphonomethylpyridine-2-Carboxylatesen
dcterms.bibliographicCitationHinchliffe, P., Tanner, C. A., Krismanich, A. P., Labbé, G., Goodfellow, V. J., Marrone, L., … Dmitrienko, G. I. (2018). Structural and Kinetic Studies on the Potent Inhibition of Metallo-β-Lactamases by 6-Phosphonomethylpyridine-2-Carboxylates. Biochemistry.
uws.contributor.affiliation1Faculty of Scienceen

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