title: Peptide deformylase inhibitors of Mycobacterium tuberculosis: synthesis, structural investigations, and biological results.
abstract: Bacterial peptide deformylase (PDF) belongs to a subfamily of metalloproteases catalyzing the removal of the N-terminal formyl group from newly synthesized proteins. We report the synthesis and biological activity of highly potent inhibitors of Mycobacterium tuberculosis (Mtb) PDF enzyme as well as the first X-ray crystal structure of Mtb PDF. Structure-activity relationship and crystallographic data clarified the structural requirements for high enzyme potency and cell based potency. Activities against single and multi-drug-resistant Mtb strains are also reported.
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Road, #05-01 Chromos, Singapore 138670, Singapore. arkadius.pichota@novartis.com
authors.forename: Arkadius
authors.initials: A
authors.lastname: Pichota
authors.forename: Jeyaraj
authors.initials: J
authors.lastname: Duraiswamy
authors.forename: Zheng
authors.initials: Z
authors.lastname: Yin
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
authors.forename: Jenefer
authors.initials: J
authors.lastname: Alam
authors.forename: Sarah
authors.initials: S
authors.lastname: Liung
authors.forename: Gladys
authors.initials: G
authors.lastname: Lee
authors.forename: Mei
authors.initials: M
authors.lastname: Ding
authors.forename: Gang
authors.initials: G
authors.lastname: Wang
authors.forename: Wai Ling
authors.initials: WL
authors.lastname: Chan
authors.forename: Mark
authors.initials: M
authors.lastname: Schreiber
authors.forename: Ida
authors.initials: I
authors.lastname: Ma
authors.forename: David
authors.initials: D
authors.lastname: Beer
authors.forename: Xinyi
authors.initials: X
authors.lastname: Ngew
authors.forename: Kakoli
authors.initials: K
authors.lastname: Mukherjee
authors.forename: Mahesh
authors.initials: M
authors.lastname: Nanjundappa
authors.forename: Jeanette W P
authors.initials: JW
authors.lastname: Teo
authors.forename: Pamela
authors.initials: P
authors.lastname: Thayalan
authors.forename: Amelia
authors.initials: A
authors.lastname: Yap
authors.forename: Thomas
authors.initials: T
authors.lastname: Dick
authors.forename: Wuyi
authors.initials: W
authors.lastname: Meng
authors.forename: Mei
authors.initials: M
authors.lastname: Xu
authors.forename: James
authors.initials: J
authors.lastname: Koehn
authors.forename: Shi-Hao
authors.initials: SH
authors.lastname: Pan
authors.forename: Kirk
authors.initials: K
authors.lastname: Clark
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xie
authors.forename: Carolyn
authors.initials: C
authors.lastname: Shoen
authors.forename: Michael
authors.initials: M
authors.lastname: Cynamon
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D000995:Antitubercular Agents / Q000737:chemistry / Q000627:therapeutic use*; D002626:Chemistry, Pharmaceutical / Q000379:methods; D018360:Crystallography, X-Ray / Q000379:methods; D015195:Drug Design; D018432:Drug Resistance, Multiple; D024841:Fluoroquinolones / Q000494:pharmacology; D000077734:Gatifloxacin; D006801:Humans; D020128:Inhibitory Concentration 50; D008826:Microbial Sensitivity Tests; D008956:Models, Chemical; D008968:Molecular Conformation; D009163:Mycobacterium bovis / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy*
chemical_list: D000995:Antitubercular Agents; D024841:Fluoroquinolones; D000581:Amidohydrolases; C084507:peptide deformylase; D000077734:Gatifloxacin