Discovery of a cofactor-independent inhibitor of<i>Mycobacterium tuberculosis</i>InhA

Xia, Yi; Zhou, Yasheen; Carter, David S.; McNeil, Matthew B.; Choi, Wai; Halladay, Jason; Berry, Pamela; Mao, Wenzhe; Hernandez, Vincent; O'Malley, Theresa; Korkegian, Aaron; Sunde, Bjorn; Flint, Lindsay; Woolhiser, Lisa K.; Scherman, Michael S.; Gruppo, Veronica; Hastings, Courtney; Robertson, Gregory T.; Ioerger, Thomas R.; Sacchettini, J.C.; Tonge, Peter J.; Lenaerts, Anne J.; Parish, Tanya; Alley, M. R. K.

doi:10.26508/lsa.201800025

Cited by 36 publications

(50 citation statements)

References 32 publications

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“…Isoniazid is a prodrug and its activation in a cell is performed by catalaseperoxidase, coded by the katG gene in M. tuberculosis (9). Mutations in the inhA regulatory region are known to induce overexpression of inhA and promote INH resistance by increasing the number of target molecules (7,10). Mutations in the katG and inhA genes are most clinically relevant and determine resistance in most clinical isolates (11,12).…”

Section: Discussionmentioning

confidence: 99%

Genotypic Characterization of katG, inhA, and ahpC in Isoniazid-Resistant Mycobacterium tuberculosis Clinical Isolates in Shanghai, China

Cao

Zhan

Guo

et al. 2020

Jundishapur J Microbiol

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Background: Mycobacterium tuberculosis is a pathogen that causes Tuberculosis and can invade various organs in infected patients. Its high morbidity and high mortality seriously threaten human health. In recent years, the continuous emergence of drug-resistant Tuberculosis bacteria has brought severe challenges to the prevention and control of Tuberculosis. Objectives: This study aimed to characterize the most frequent mutations of the katG, inhA, and ahpC genes in isoniazid (INH)resistant M. tuberculosis clinical isolates in Shanghai Pulmonary Hospital, China, and investigate the relationship between gene mutations and the minimum inhibitory concentrations (MICs) of INH against M. tuberculosis. Methods: We collected 92 INH-resistant and 30 INH-susceptible clinical isolates of M. tuberculosis. The drug resistance profiles of M. tuberculosis clinical isolates against common anti-tuberculosis drugs were determined and sequencing analysis was performed. Results: Of 92 INH-resistant strains, mutations in the katG and inhA genes were observed in 64 (69.6%) isolates and five (5.4%) isolates, respectively, and only had one (1.1%) strain both katG and inhA mutations. Among them, 62 (67.4%) strains carried a single mutation at codon 315 of the katG gene and a new mutation site was found in the katG gene of two strains. We detected a single mutation site at codon 271 and three simultaneous mutation sites at codons 315, 431, and 439. Only one (3.3%) of the 30 isoniazid-sensitive strains had the katG mutation. The AhpC mutation was detected in no experimental strains. The KatG Ser 315 Thr (AGC315ACC) mutation occurred in 53 (68.8%) out of 77 strains with high MICs (≥ 1 g/mL) of isoniazid-resistant M. tuberculosis while five (33.3%) out of 15 strains with low MICs (less than 1 g/mL) had katG Ser 315 Thr (AGC315ACC) mutation. Conclusions: Isoniazid-resistant strains were dominated by Ser315 → Thr (AGC → ACC) substitution, which seems to be associated with multidrug resistance and high-level resistance to INH. Multisite mutations are related to multidrug-resistant M. tuberculosis and the discovery of new mutation sites provides a new basis for the detection of drug-resistant M. tuberculosis.

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Section: Discussionmentioning

confidence: 99%

Genotypic Characterization of katG, inhA, and ahpC in Isoniazid-Resistant Mycobacterium tuberculosis Clinical Isolates in Shanghai, China

Cao

Zhan

Guo

et al. 2020

Jundishapur J Microbiol

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“…With KatG being a major factor in INH resistance and a potential player in INH shortcoming in dormant M. tuberculosis, new InhA inhibitors that would not require activation by KatG have been actively sought [82][83][84][85][86][87][88][89]. Compounds such as GlaxoSmithKline's thiadiazole GSK693 [90] or the diazaborine AN12855 [91,92] are promising leads with good oral bioavailability, low toxicity, activity against katG-deficient M. tuberculosis and in vivo efficacy similar to INH. EMB is a first-line TB drug, given for the first two months of TB treatment alongside INH, RIF and PZA.…”

Section: Old Tb Drugsmentioning

confidence: 99%

“…Academic and pharmaceutical laboratories are developing new inhibitors of enzymes involved in mycolic acid biosynthesis. Inhibitors of KasA [213], InhA [83,[90][91][92], Pks13 [214][215][216][217] and Mmpl3 [185,190,191,218,219] are being tested.…”

Section: Delamanid (Opc-67683)mentioning

confidence: 99%

Mycobacterial Cell Wall: A Source of Successful Targets for Old and New Drugs

Vilchèze

2020

Applied Sciences

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Eighty years after the introduction of the first antituberculosis (TB) drug, the treatment of drug-susceptible TB remains very cumbersome, requiring the use of four drugs (isoniazid, rifampicin, ethambutol and pyrazinamide) for two months followed by four months on isoniazid and rifampicin. Two of the drugs used in this “short”-course, six-month chemotherapy, isoniazid and ethambutol, target the mycobacterial cell wall. Disruption of the cell wall structure can enhance the entry of other TB drugs, resulting in a more potent chemotherapy. More importantly, inhibition of cell wall components can lead to mycobacterial cell death. The complexity of the mycobacterial cell wall offers numerous opportunities to develop drugs to eradicate Mycobacterium tuberculosis, the causative agent of TB. In the past 20 years, researchers from industrial and academic laboratories have tested new molecules to find the best candidates that will change the face of TB treatment: drugs that will shorten TB treatment and be efficacious against active and latent, as well as drug-resistant TB. Two of these new TB drugs block components of the mycobacterial cell wall and have reached phase 3 clinical trial. This article reviews TB drugs targeting the mycobacterial cell wall in use clinically and those in clinical development.

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“…persisters (3). We have previously identified a diazaborine series with potential for development as a new tuberculosis drug (4,5). This series has activity in vitro and in vivo and targets cell wall biosynthesis via inhibition of InhA (4).…”

mentioning

confidence: 99%

“…We have previously identified a diazaborine series with potential for development as a new tuberculosis drug (4,5). This series has activity in vitro and in vivo and targets cell wall biosynthesis via inhibition of InhA (4). Diazaborine activity does not require a cofactor or require activation by bacterial enzymes (unlike the frontline drug isoniazid which also targets InhA) and so the series has improved properties and a lower frequency of resistance than isoniazid.…”

mentioning

confidence: 99%

InhA inhibitors have activity against non-replicatingMycobacterium tuberculosis

Flint

Korkegian

Parish

2020

Preprint

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We previously identified a diazaborine series with potential for development as a new tuberculosis drug. This series has activity in vitro and in vivo and targets cell wall biosynthesis via inhibition of InhA. We tested the ability of two molecules of the diazaborine series to kill non-replicating Mycobacterium tuberculosis in the nutrient starvation model; both molecules were bactericidal, reducing viability by >3 logs in 21 days. Activity showed similar kill rates to other InhA inhibitors (isoniazid and NITD-916). We conclude that inhibition of InhA is bactericidal against nutrient-starved non-replicating M. tuberculosis.

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Discovery of a cofactor-independent inhibitor ofMycobacterium tuberculosisInhA

Abstract: AN12855 is a novel cofactor-independent inhibitor of Mycobacterium tuberculosis InhA. AN12855 has potent activity against M. tuberculosis, good oral bioavailability, and comparable efficacy to isoniazid in infection models.

Cited by 36 publications

References 32 publications

Genotypic Characterization of katG, inhA, and ahpC in Isoniazid-Resistant Mycobacterium tuberculosis Clinical Isolates in Shanghai, China

Genotypic Characterization of katG, inhA, and ahpC in Isoniazid-Resistant Mycobacterium tuberculosis Clinical Isolates in Shanghai, China

Mycobacterial Cell Wall: A Source of Successful Targets for Old and New Drugs

InhA inhibitors have activity against non-replicatingMycobacterium tuberculosis

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