TitleTargeting Enterococcus faecalis HMG-CoA reductase with a non-statin inhibitor.
Publication TypeJournal Article
Year of Publication2023
AuthorsBose S, C Steussy N, López-Pérez D, Schmidt T, Kulathunga SC, Seleem MN, Lipton M, Mesecar AD, Rodwell VW, Stauffacher CV
JournalCommun Biol
Date Published2023 Apr 03
KeywordsAcyl Coenzyme A, Enterococcus faecalis, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Mevalonic Acid

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 Å 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.

Alternate JournalCommun Biol
PubMed ID37012403
PubMed Central IDPMC10070635
Grant ListP30 CA023168 / CA / NCI NIH HHS / United States
P30 GM138396 / GM / NIGMS NIH HHS / United States
R01 GM111645 / GM / NIGMS NIH HHS / United States
R03 MH082373 / MH / NIMH NIH HHS / United States