title: Identification of novel inhibitors of the streptogramin group A acetyltransferase via virtual screening.
abstract: Virginiamycin acetyltransferase D (VatD) plays a vital rule in streptogramins resistance by chemically inactivating streptogramin A. Therefore, it is desirable to discover novel small molecular weight inhibitors of VatD via state-of-the-art virtual screening techniques. This "cocktail" strategy by combining VatD inhibitor with streptogramins may provide new therapeutic opportunity for resistant bacteria infections. Structure-based virtual screening method (molecular docking) was applied to rank and score a chemical database containing 300 000 commercially available compounds against the VatD substrate binding site. Twenty six out of the 200 top scored compounds from the docking calculation were selected and submitted to the VatD enzymatic inhibition assay. The plasmid pRSET B/vatD was constructed and transformed into E. coli (trxB) host cells for over-expression, and VatD enzyme was purified and validated by showing acetyltransferase activity to Virginiamycin M1. Three out of these 26 tested compounds showed enzymatic inhibition on VatD with IC50 168.6, 91.0 and 55.2 micromol x L(-1), separately. Other compounds could not be dissolved in the system and/or had little effect on the enzyme (IC50 > 200 micromol x L(-1)). To our knowledge, it is first time that small molecular weight organic compounds were identified as VatD inhibitors. It is expected that the VatD inhibitors identified at present study could serve as lead compounds for the further development of the novel therapeutic agents to overcome streptogramins resistance.
authors.affiliation: Shanghai Institute of Pharmaceutical Industry, Shanghai 200437, China.
authors.forename: Guang-Feng
authors.initials: GF
authors.lastname: Wang
authors.forename: Niu
authors.initials: N
authors.lastname: Huang
authors.forename: Zhi-Hong
authors.initials: ZH
authors.lastname: Meng
authors.forename: Quan-Hai
authors.initials: QH
authors.lastname: Liu
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D002384:Catalysis / Q000187:drug effects; D015195:Drug Design; D024881:Drug Resistance, Bacterial; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004926:Escherichia coli / Q000235:genetics; D005822:Genetic Vectors; D007700:Kinetics; D015394:Molecular Structure; D010957:Plasmids; D025362:Streptogramin Group A / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014170:Transformation, Genetic
chemical_list: D004791:Enzyme Inhibitors; D025362:Streptogramin Group A; D000123:Acetyltransferases; C477287:virginiamycin acetyltransferase D