title: Structure-based design of DevR inhibitor active against nonreplicating Mycobacterium tuberculosis.
abstract: Antitubercular treatment is directed against actively replicating organisms. There is an urgent need to develop drugs targeting persistent subpopulations of Mycobacterium tuberculosis. The DevR response regulator is believed to play a key role in bacterial dormancy adaptation during hypoxia. We developed a homology-based model of DevR and used it for the rational design of inhibitors. A phenylcoumarin derivative (compound 10) identified by in silico pharmacophore-based screening of 2.5 million compounds employing protocols with some novel features including a water-based pharmacophore query, was characterized further. Compound 10 inhibited DevR binding to target DNA, down-regulated dormancy genes transcription, and drastically reduced survival of hypoxic but not nutrient-starved dormant bacteria or actively growing organisms. Our findings suggest that compound 10 "locks" DevR in an inactive conformation that is unable to bind cognate DNA and induce the dormancy regulon. These results provide proof-of-concept for DevR as a novel target to develop molecules with sterilizing activity against tubercle bacilli.
authors.affiliation: Department of Biotechnology, All India Institute of Medical Sciences, New Delhi 110029, India.
authors.forename: Rajesh Kumar
authors.initials: RK
authors.lastname: Gupta
authors.forename: Tejender S
authors.initials: TS
authors.lastname: Thakur
authors.forename: Gautam R
authors.initials: GR
authors.lastname: Desiraju
authors.forename: Jaya Sivaswami
authors.initials: JS
authors.lastname: Tyagi
mesh_terms: D000332:Aerobiosis; D000995:Antitubercular Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D019295:Computational Biology; D004269:DNA, Bacterial / Q000378:metabolism; D015195:Drug Design; D015964:Gene Expression Regulation, Bacterial / Q000187:drug effects; D000860:Hypoxia / Q000378:metabolism; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics / Q000502:physiology*; D006656:Protamine Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D011487:Protein Conformation; D017385:Sequence Homology; D014158:Transcription, Genetic / Q000187:drug effects
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004269:DNA, Bacterial; C506260:DevS protein, Mycobacterium tuberculosis; D006656:Protamine Kinase