title: Optimization of pyrrolamides as mycobacterial GyrB ATPase inhibitors: structure-activity relationship and in vivo efficacy in a mouse model of tuberculosis.
abstract: Moxifloxacin has shown excellent activity against drug-sensitive as well as drug-resistant tuberculosis (TB), thus confirming DNA gyrase as a clinically validated target for discovering novel anti-TB agents. We have identified novel inhibitors in the pyrrolamide class which kill Mycobacterium tuberculosis through inhibition of ATPase activity catalyzed by the GyrB domain of DNA gyrase. A homology model of the M. tuberculosis H37Rv GyrB domain was used for deciphering the structure-activity relationship and binding interactions of inhibitors with mycobacterial GyrB enzyme. Proposed binding interactions were later confirmed through cocrystal structure studies with the Mycobacterium smegmatis GyrB ATPase domain. The most potent compound in this series inhibited supercoiling activity of DNA gyrase with a 50% inhibitory concentration (IC50) of <5 nM, an MIC of 0.03 μg/ml against M. tuberculosis H37Rv, and an MIC90 of <0.25 μg/ml against 99 drug-resistant clinical isolates of M. tuberculosis. The frequency of isolating spontaneous resistant mutants was ∼10(-6) to 10(-8), and the point mutation mapped to the M. tuberculosis GyrB domain (Ser208 Ala), thus confirming its mode of action. The best compound tested for in vivo efficacy in the mouse model showed a 1.1-log reduction in lung CFU in the acute model and a 0.7-log reduction in the chronic model. This class of GyrB inhibitors could be developed as novel anti-TB agents.
authors.affiliation: AstraZeneca India Pvt Ltd., Hebbal, Bangalore, India.
authors.forename: Shahul Hameed
authors.initials: SH
authors.lastname: P
authors.forename: Suresh
authors.initials: S
authors.lastname: Solapure
authors.forename: Kakoli
authors.initials: K
authors.lastname: Mukherjee
authors.forename: Vrinda
authors.initials: V
authors.lastname: Nandi
authors.forename: David
authors.initials: D
authors.lastname: Waterson
authors.forename: Radha
authors.initials: R
authors.lastname: Shandil
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Balganesh
authors.forename: Vasan K
authors.initials: VK
authors.lastname: Sambandamurthy
authors.forename: Anand Kumar
authors.initials: AK
authors.lastname: Raichurkar
authors.forename: Abhijeet
authors.initials: A
authors.lastname: Deshpande
authors.forename: Anirban
authors.initials: A
authors.lastname: Ghosh
authors.forename: Disha
authors.initials: D
authors.lastname: Awasthy
authors.forename: Gajanan
authors.initials: G
authors.lastname: Shanbhag
authors.forename: Gulebahar
authors.initials: G
authors.lastname: Sheikh
authors.forename: Helen
authors.initials: H
authors.lastname: McMiken
authors.forename: Jayashree
authors.initials: J
authors.lastname: Puttur
authors.forename: Jitendar
authors.initials: J
authors.lastname: Reddy
authors.forename: Jim
authors.initials: J
authors.lastname: Werngren
authors.forename: Jon
authors.initials: J
authors.lastname: Read
authors.forename: Mahesh
authors.initials: M
authors.lastname: Kumar
authors.forename: Manjunatha
authors.initials: M
authors.lastname: R
authors.forename: Murugan
authors.initials: M
authors.lastname: Chinnapattu
authors.forename: Prashanti
authors.initials: P
authors.lastname: Madhavapeddi
authors.forename: Praveena
authors.initials: P
authors.lastname: Manjrekar
authors.forename: Reetobrata
authors.initials: R
authors.lastname: Basu
authors.forename: Sheshagiri
authors.initials: S
authors.lastname: Gaonkar
authors.forename: Sreevalli
authors.initials: S
authors.lastname: Sharma
authors.forename: Sven
authors.initials: S
authors.lastname: Hoffner
authors.forename: Vaishali
authors.initials: V
authors.lastname: Humnabadkar
authors.forename: Venkita
authors.initials: V
authors.lastname: Subbulakshmi
authors.forename: Vijender
authors.initials: V
authors.lastname: Panduga
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D002460:Cell Line; D006801:Humans; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000187:drug effects / Q000472:pathogenicity*; D013329:Structure-Activity Relationship; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents