title: Mechanism-based inhibition of HsaD: a C-C bond hydrolase essential for survival of Mycobacterium tuberculosis in macrophage.
abstract: Mycobacterium tuberculosis remains the leading cause of death by a bacterial pathogen worldwide. Increasing prevalence of multidrug-resistant organisms means prioritizing identification of targets for antituberculars. 2-hydroxy-6-oxo-6-phenylhexa-2,4-dienoate hydrolase (HsaD), part of the cholesterol metabolism operon, is vital for survival within macrophage. The C-C bond hydrolase, HsaD, has a serine protease-like catalytic triad. We tested a range of serine protease and esterase inhibitors for their effects on HsaD activity. As well as providing a potential starting point for drug development, the data provides evidence for the mechanism of C-C bond hydrolysis. This screen also provides a route to initiate development of fragment-based inhibitors.
authors.affiliation: Faculty of Science Engineering and Computing, Kingston University, Kingston, UK; Department of Pharmacology, University of Oxford, Oxford, UK.
authors.forename: Ali
authors.initials: A
authors.lastname: Ryan
authors.forename: Sebastian
authors.initials: S
authors.lastname: Keany
authors.forename: Olga
authors.initials: O
authors.lastname: Eleftheriadou
authors.forename: Romain
authors.initials: R
authors.lastname: Ballet
authors.forename: Hung-Yuan
authors.initials: HY
authors.lastname: Cheng
authors.forename: Edith
authors.initials: E
authors.lastname: Sim
mesh_terms: D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D002800:Cholinesterase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D005231:Fatty Acids, Unsaturated / Q000378:metabolism*; D006867:Hydrolases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D006868:Hydrolysis; D020128:Inhibitory Concentration 50; D008264:Macrophages / Q000382:microbiology; D050296:Microbial Viability; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D011487:Protein Conformation; D011549:Pseudomonas / Q000235:genetics / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D000995:Antitubercular Agents; D002800:Cholinesterase Inhibitors; D005231:Fatty Acids, Unsaturated; D015842:Serine Proteinase Inhibitors; C018971:2-hydroxy-6-oxo-6-phenyl-2,4-hexadienoic acid; D006867:Hydrolases; C527647:HsaD protein, Mycobacterium tuberculosis
keywords: HsaD; MCP hydrolase; Mycobacterium tuberculosis; cholesterol; inhibitors; mechanism