Direct inhibitors of InhA are active against
            <i>Mycobacterium tuberculosis</i>

Manjunatha, Ujjini H.; Rao, Srinivasa P. S.; Kondreddi, Ravinder Reddy; Noble, Christian G.; Camacho, Luis R.; Tan, Bee Huat; Ng, Seow Hwee; Ng, Pearly Shuyi; Ng, Leong L.; Lakshminarayana, Suresh B.; Hervé, Maxime; Barnes, S. Whitney; Yu, Weixuan; Kuhen, Kelli; Blasco, Francesca; Beer, David; Walker, John R.; Tonge, Peter J.; Glynne, Richard; Smith, Paul W.; Diagana, Thierry T.

doi:10.1126/scitranslmed.3010597

Cited by 110 publications

(102 citation statements)

References 38 publications

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“…The proven druggability of InhA in the treatment of M. tuberculosis has prompted research into direct inhibitors of InhA that overcome such INH liabilities as the requirement for KatG activation and the high rate of resistance (2). Several direct InhA inhibitors have been identified, including the thiadiazoles (GSK693) (3), 2-(o-tolyloxy)-5-hexylphenol (PT70) (4), and the 4-hydroxy-2-pyridines (NITD-916 and NITD-113) (3–5). Unlike the INH-NAD adduct that competes with NADH binding to InhA, NITD-916 forms a ternary complex with InhA and NADH to block access to the fatty acyl substrate binding pocket (5).…”

mentioning

confidence: 99%

Mechanisms of resistance against NITD-916, a direct inhibitor of Mycobacterium tuberculosis InhA

et al. 2017

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Summary Isoniazid inhibits Mycobacterium tuberculosis InhA and is a key component of drug regimens that treat tuberculosis. However, the high rate of resistance against isoniazid is a contributing factor to the emergence of multi-drug resistance strains of M. tuberculosis. The 4-hydroxy-2-pyridine NITD-916 is a direct inhibitor of M. tuberculosis InhA that has comparable efficacy to isoniazid in mouse models of TB infection but a lower frequency of resistance. To characterize resistance mechanisms against NITD-916 we isolated resistant mutants in H37Rv (Euro-American lineage) and HN878 (East-Asian lineage) strains of M. tuberculosis. The resistance frequency was similar in both strains. Mutations were identified in residues within or near to the active of InhA or in the fabG1inhA promoter region. All mutants were resistant to NITD-916 but were not cross resistant to isoniazid, despite homology to SNPs identified in isoniazid resistant clinical isolates.

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confidence: 99%

Mechanisms of resistance against NITD-916, a direct inhibitor of Mycobacterium tuberculosis InhA

et al. 2017

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“…(5) Pyrazole ELT hit (13). (6) Pyridine dione (27). off-DNA synthesis based on potential mechanism of action, enrichment level, and their physicochemical properties.…”

Section: Significancementioning

confidence: 99%

Discovery of cofactor-specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library technology

Soutter¹,

Centrella²,

Clark

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Millions of individuals are infected with and die from tuberculosis (TB) each year, and multidrug-resistant (MDR) strains of TB are increasingly prevalent. As such, there is an urgent need to identify novel drugs to treat TB infections. Current frontline therapies include the drug isoniazid, which inhibits the essential NADH-dependent enoyl–acyl-carrier protein (ACP) reductase, InhA. To inhibit InhA, isoniazid must be activated by the catalase-peroxidase KatG. Isoniazid resistance is linked primarily to mutations in the katG gene. Discovery of InhA inhibitors that do not require KatG activation is crucial to combat MDR TB. Multiple discovery efforts have been made against InhA in recent years. Until recently, despite achieving high potency against the enzyme, these efforts have been thwarted by lack of cellular activity. We describe here the use of DNA-encoded X-Chem (DEX) screening, combined with selection of appropriate physical properties, to identify multiple classes of InhA inhibitors with cell-based activity. The utilization of DEX screening allowed the interrogation of very large compound libraries (1011 unique small molecules) against multiple forms of the InhA enzyme in a multiplexed format. Comparison of the enriched library members across various screening conditions allowed the identification of cofactor-specific inhibitors of InhA that do not require activation by KatG, many of which had bactericidal activity in cell-based assays.

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“…A pyridone, NITD-916, inhibits the clinically validated target InhA but, unlike the long-used antibiotic isoniazid, does not require activation by catalaseperoxidase KatG 21 . Two indolcarboxamide analogues, NITD-304 and NITD-349, are potent against drug-sensitive and multidrugresistant isolates.…”

Section: Inhibitors Of Tuberculosis Metabolismmentioning

confidence: 99%

“…The NITD has carried out three phenotypic screens against Mycobacterium spp., which have culminated in five promising series: pyrimidine imidazoles 17 , imidazopyridines 18 , pyrazolopyrimidines 19 , indolcarboxamides 20 and pyridones 21 .…”

Section: Inhibitors Of Tuberculosis Metabolismmentioning

confidence: 99%

Drug discovery for the developing world: progress at the Novartis Institute for Tropical Diseases

Jones

Yeung

Manjunatha

et al. 2015

Nat Rev Drug Discov

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Direct inhibitors of InhA are active against Mycobacterium tuberculosis

Cited by 110 publications

References 38 publications

Mechanisms of resistance against NITD-916, a direct inhibitor of Mycobacterium tuberculosis InhA

Mechanisms of resistance against NITD-916, a direct inhibitor of Mycobacterium tuberculosis InhA

Discovery of cofactor-specific, bactericidal Mycobacterium tuberculosis InhA inhibitors using DNA-encoded library technology

Drug discovery for the developing world: progress at the Novartis Institute for Tropical Diseases

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