Department of Biological Sciences, Purdue University, 915 West State Street, West Lafayette, IN, 47907, USA.
Institute for Stem Cell Science and Regenerative Medicine, GKVK Post Bellary Road, Bangalore, 560065, India.
Commun Biol. 2023 Apr 3;6(1):360. doi: 10.1038/s42003-023-04639-y.
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.
HMG-CoA 还原酶（HMGR）是革兰氏阳性致病菌甲羟戊酸途径中的限速酶，是开发新型抗生素的有吸引力的靶标。在这项研究中，我们报告了粪肠球菌（efHMGR）HMGR 在无配体和配体结合形式下的晶体结构，突出了该酶的几个独特特征。以纳摩尔亲和力抑制人酶的他汀类药物对细菌 HMGR 同源物的作用效果不佳。我们还报告了通过高通量体外筛选鉴定的 efHMGR 酶的一种有效的竞争性抑制剂（Chembridge2 ID 7828315 或化合物 315）。通过 X 射线晶体学确定了 efHMGR 与 315 的复合物的结构，分辨率为 1.27Å，揭示了抑制剂占据了甲羟戊酸结合位点，并与细菌同源物中保守的几个关键活性位点残基相互作用。重要的是，315 不会抑制人 HMGR。我们鉴定出了一种选择性、非他汀类的细菌 HMG-CoA 还原酶抑制剂，这将有助于新型抗菌药物候选物的先导优化和开发。
