Structure-activity relationship studies for inhibitors for vancomycin-resistant Enterococcus and human carbonic anhydrases

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dc.contributor.authorAn, Weiweien
dc.contributor.authorHolly, Katrina J.en
dc.contributor.authorNocentini, Alessioen
dc.contributor.authorImhoff, Ryan D.en
dc.contributor.authorHewitt, Chad. S.en
dc.contributor.authorAbutaleb, Nader S.en
dc.contributor.authorCao, Xufengen
dc.contributor.authorSeleem, Mohamed N.en
dc.contributor.authorSupuran, Claudiu T.en
dc.contributor.authorFlaherty, Daniel P.en
dc.date.accessioned2022-10-04T16:46:22Zen
dc.date.available2022-10-04T16:46:22Zen
dc.date.issued2022-12-31en
dc.description.abstractVancomycin-resistant enterococci (VRE), consisting of pathogenic Enterococcus faecalis and E. faecium, is a leading cause of hospital-acquired infections (HAIs). We recently repurposed the FDA-approved human carbonic anhydrase (CA) inhibitor acetazolamide (AZM) against VRE agent with the likely mechanism of action for the molecules being inhibition of one, or both, of the bacterial CA isoforms expressed in VRE. To elucidate how inhibitor binding to the enzymes relates to MIC, we further characterised the inhibition constants (K (i)) against the E. faecium alpha-CA (Ef alpha-CA) and gamma-CA (Ef gamma-CA), as well as against human CA I (hCAI) and human CA II (hCAII) to assess selectivity. We have also utilised homology modelling and molecular dynamics (MD) simulations to gain a better understanding of the potential interactions the molecules are making with the targets. In this paper, we elaborate on the SAR for the AZM analogs as it pertains to MIC and K (i) for each CA.en
dc.description.notesThe research program was partially funded by a Purdue Institute for Drug Discovery Programmatic [Grant (M.N.S and D.P.F.) and NIH/NIAID 1R01AI148523 (M.N.S and D.P.F.)]. This work was also supported by the Italian Ministry for University and Research, [grant FISR2019_04819 BacCAD (C.T.S.)].en
dc.description.sponsorshipPurdue Institute for Drug Discovery Programmatic; NIH/NIAID [1R01AI148523]; Italian Ministry for University and Research [FISR2019_04819]en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1080/14756366.2022.2092729en
dc.identifier.eissn1475-6374en
dc.identifier.issn1475-6366en
dc.identifier.issue1en
dc.identifier.pmid35758212en
dc.identifier.urihttp://hdl.handle.net/10919/112066en
dc.identifier.volume37en
dc.language.isoenen
dc.publisherTaylor & Francisen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectCarbonic anhydrase inhibitorsen
dc.subjectvancomycin-resistant Enterococcusen
dc.subjectantibioticsen
dc.subjectdrug repurposingen
dc.titleStructure-activity relationship studies for inhibitors for vancomycin-resistant Enterococcus and human carbonic anhydrasesen
dc.title.serialJournal of Enzyme Inhibition and Medicinal Chemistryen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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