Targeting Enterococcus faecalis HMG-CoA reductase with a non-statin inhibitor

dc.contributor.authorBose, Sucharitaen
dc.contributor.authorSteussy, C. Nicklausen
dc.contributor.authorLopez-Perez, Danelien
dc.contributor.authorSchmidt, Timen
dc.contributor.authorKulathunga, Samadhi C.en
dc.contributor.authorSeleem, Mohamed N.en
dc.contributor.authorLipton, Marken
dc.contributor.authorMesecar, Andrew D.en
dc.contributor.authorRodwell, Victor W.en
dc.contributor.authorStauffacher, Cynthia V.en
dc.date.accessioned2023-09-12T14:31:15Zen
dc.date.available2023-09-12T14:31:15Zen
dc.date.issued2023-04en
dc.description.abstractHigh-throughput in vitro screening and crystal structures identify a non-statin inhibitor of HMG-CoA reductase for novel antibacterial drug design. HMG-CoA reductase (HMGR), a rate-limiting enzyme of the mevalonate pathway in Gram-positive pathogenic bacteria, is an attractive target for development of novel antibiotics. In this study, we report the crystal structures of HMGR from Enterococcus faecalis (efHMGR) in the apo and liganded forms, highlighting several unique features of this enzyme. Statins, which inhibit the human enzyme with nanomolar affinity, perform poorly against the bacterial HMGR homologs. We also report a potent competitive inhibitor (Chembridge2 ID 7828315 or compound 315) of the efHMGR enzyme identified by a high-throughput, in-vitro screening. The X-ray crystal structure of efHMGR in complex with 315 was determined to 1.27 angstrom resolution revealing that the inhibitor occupies the mevalonate-binding site and interacts with several key active site residues conserved among bacterial homologs. Importantly, 315 does not inhibit the human HMGR. Our identification of a selective, non-statin inhibitor of bacterial HMG-CoA reductases will be instrumental in lead optimization and development of novel antibacterial drug candidates.en
dc.description.notesThis work was supported by the National Institutes of Health grants R01 GM111645 and R03 MH082373 to C.V.S. The research used resources of the Advanced Photon Source, a U.S. Department of Energy (DOE) Office of Science User Facility, operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-Ac02-0CH11357. Data was collected on the APS GM/CA beamline; GM/CA@APS has been funded by the National Cancer Institute (ACD-12002) and the National Institute of General Medical Sciences (AGM-1200, P30GM138396). The authors gratefully acknowledge the support of the Macromolecular X-ray Diffraction Facility in the Purdue Center for Cancer Research, P30 CA023168. We would like to thank the Hauptman Woodward crystal screening facility for the initial high-throughput screening of crystallization conditions and Dr. Lucille White from the Southern Research Institute, Alabama for performing the high throughput screening assays of compounds with efHMGR. This publication was written by D.L.P. in a personal capacity and does not represent the opinions of the Food and Drug Administration, the Department of Health and Human Services, nor the Federal Government.en
dc.description.sponsorshipNational Institutes of Health [R01 GM111645, R03 MH082373]; DOE Office of Science by Argonne National Laboratory [DE-Ac02-0CH11357]; National Cancer Institute [ACD-12002]; National Institute of General Medical Sciences [AGM-1200, P30GM138396]; Purdue Center for Cancer Research [P30 CA023168]en
dc.description.versionPublished versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1038/s42003-023-04639-yen
dc.identifier.eissn2399-3642en
dc.identifier.issue1en
dc.identifier.other360en
dc.identifier.pmid37012403en
dc.identifier.urihttp://hdl.handle.net/10919/116265en
dc.identifier.volume6en
dc.language.isoenen
dc.publisherNature Portfolioen
dc.rightsCreative Commons Attribution 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectvancomycin-resistant enterococcusen
dc.subjectcoenzyme-a reductaseen
dc.subjectcrystal-structureen
dc.subjectcatalytic portionen
dc.subjecthydride transferen
dc.subjectbinding folden
dc.subjectdomainen
dc.subjectbiosynthesisen
dc.subjectspecificityen
dc.subjectessentialityen
dc.titleTargeting Enterococcus faecalis HMG-CoA reductase with a non-statin inhibitoren
dc.title.serialCommunications Biologyen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten
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