title: Direct inhibitors of InhA are active against Mycobacterium tuberculosis.
abstract: New chemotherapeutic agents are urgently required to combat the global spread of multidrug-resistant tuberculosis (MDR-TB). The mycobacterial enoyl reductase InhA is one of the few clinically validated targets in tuberculosis drug discovery. We report the identification of a new class of direct InhA inhibitors, the 4-hydroxy-2-pyridones, using phenotypic high-throughput whole-cell screening. This class of orally active compounds showed potent bactericidal activity against common isoniazid-resistant TB clinical isolates. Biophysical studies revealed that 4-hydroxy-2-pyridones bound specifically to InhA in an NADH (reduced form of nicotinamide adenine dinucleotide)-dependent manner and blocked the enoyl substrate-binding pocket. The lead compound NITD-916 directly blocked InhA in a dose-dependent manner and showed in vivo efficacy in acute and established mouse models of Mycobacterium tuberculosis infection. Collectively, our structural and biochemical data open up new avenues for rational structure-guided optimization of the 4-hydroxy-2-pyridone class of compounds for the treatment of MDR-TB.
authors.affiliation: Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore. Yong Loo Lin School of Medicine, National University of Singapore, 119228 Singapore, Singapore. manjunatha.ujjini@novartis.com thierry.diagana@novartis.com.
authors.forename: Ujjini H
authors.initials: UH
authors.lastname: Manjunatha
authors.affiliation: Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore.
authors.forename: Srinivasa P
authors.initials: SP
authors.lastname: S Rao
authors.affiliation: Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore.
authors.forename: Ravinder Reddy
authors.initials: RR
authors.lastname: Kondreddi
authors.affiliation: Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore.
authors.forename: Christian G
authors.initials: CG
authors.lastname: Noble
authors.affiliation: Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore.
authors.forename: Luis R
authors.initials: LR
authors.lastname: Camacho
authors.affiliation: Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore.
authors.forename: Bee H
authors.initials: BH
authors.lastname: Tan
authors.affiliation: Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore.
authors.forename: Seow H
authors.initials: SH
authors.lastname: Ng
authors.affiliation: Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore.
authors.forename: Pearly Shuyi
authors.initials: PS
authors.lastname: Ng
authors.affiliation: Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore.
authors.forename: Ng L
authors.initials: NL
authors.lastname: Ma
authors.affiliation: Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore.
authors.forename: Suresh B
authors.initials: SB
authors.lastname: Lakshminarayana
authors.affiliation: Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore.
authors.forename: Maxime
authors.initials: M
authors.lastname: Herve
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: Susan W
authors.initials: SW
authors.lastname: Barnes
authors.affiliation: Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Weixuan
authors.initials: W
authors.lastname: Yu
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: Kelli
authors.initials: K
authors.lastname: Kuhen
authors.affiliation: Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore.
authors.forename: Francesca
authors.initials: F
authors.lastname: Blasco
authors.affiliation: Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore.
authors.forename: David
authors.initials: D
authors.lastname: Beer
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Walker
authors.affiliation: Institute of Chemical Biology & Drug Discovery, Stony Brook University, Stony Brook, NY 11794-3400, USA.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Tonge
authors.affiliation: Genomics Institute of the Novartis Research Foundation, San Diego, CA 92121, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Glynne
authors.affiliation: Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Smith
authors.affiliation: Novartis Institute for Tropical Diseases, 138670 Singapore, Singapore. Yong Loo Lin School of Medicine, National University of Singapore, 119228 Singapore, Singapore. manjunatha.ujjini@novartis.com thierry.diagana@novartis.com.
authors.forename: Thierry T
authors.initials: TT
authors.lastname: Diagana
mesh_terms: D000818:Animals; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D055592:Biophysical Phenomena / Q000187:drug effects; D018360:Crystallography, X-Ray; D004195:Disease Models, Animal; D024901:Drug Resistance, Multiple, Bacterial / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics / Q000302:isolation & purification; D010088:Oxidoreductases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000737:chemistry / Q000494:pharmacology; D015203:Reproducibility of Results; D017422:Sequence Analysis, DNA; D018088:Tuberculosis, Multidrug-Resistant / Q000188:drug therapy / Q000382:microbiology
chemical_list: D000995:Antitubercular Agents; D001426:Bacterial Proteins; D004791:Enzyme Inhibitors; D011725:Pyridines; C039659:2,4-dihydroxypyridine; D010088:Oxidoreductases; C085257:InhA protein, Mycobacterium