title: Identification and characterisation of small-molecule inhibitors of Rv3097c-encoded lipase (LipY) of Mycobacterium tuberculosis that selectively inhibit growth of bacilli in hypoxia.
abstract: The mycobacterial Rv3097c-encoded lipase LipY is considered as a true lipase involved in the hydrolysis of triacylglycerol stored in lipid inclusion bodies for the survival of dormant mycobacteria. To date, orlistat is the only known LipY inhibitor. In view of the important emerging role of this enzyme, a search for small-molecule inhibitors of LipY was made, leading to the identification of some new compounds (8a-8d, 8f, 8h and 8i) with potent inhibitory activities against recombinant LipY, with no cytotoxicity [50% inhibitory concentration (CC(50)) ≥ 500 μg/mL]. The compounds 6a, 8c and 8f potently inhibited (>90%) the growth of Mycobacterium tuberculosis H37Rv grown under hypoxia (oxygen-depleted condition) but had no effect on aerobically grown bacilli, suggesting that these new small molecules are highly selective towards the growth inhibition of hypoxic cultures of M. tuberculosis and hence provide new leads for combating latent tuberculosis.
authors.affiliation: Division of Medicinal and Process Chemistry, CSIR Central Drug Research Institute, Lucknow 226 001, India. anilsak@gmail.com
authors.forename: Anil K
authors.initials: AK
authors.lastname: Saxena
authors.forename: Kuldeep K
authors.initials: KK
authors.lastname: Roy
authors.forename: Supriya
authors.initials: S
authors.lastname: Singh
authors.forename: S P
authors.initials: SP
authors.lastname: Vishnoi
authors.forename: Anil
authors.initials: A
authors.lastname: Kumar
authors.forename: Vivek Kr
authors.initials: VK
authors.lastname: Kashyap
authors.forename: Laurent
authors.initials: L
authors.lastname: Kremer
authors.forename: Ranjana
authors.initials: R
authors.lastname: Srivastava
authors.forename: Brahm S
authors.initials: BS
authors.lastname: Srivastava
mesh_terms: D000693:Anaerobiosis; D000818:Animals; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism* / Q000633:toxicity; D008049:Lipase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D050296:Microbial Viability / Q000187:drug effects; D008958:Models, Molecular; D015394:Molecular Structure; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D011487:Protein Conformation; D014709:Vero Cells
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D008049:Lipase