Elsevier

EBioMedicine

Volume 8, June 2016, Pages 291-301
EBioMedicine

Antitubercular drugs for an old target: GSK693 as a promising InhA direct inhibitor

https://doi.org/10.1016/j.ebiom.2016.05.006Get rights and content
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Highlights

  • KatG-independent InhA inhibitors mimicking isoniazid cidality

  • GSK693 first DI showing oral in vivo efficacy similar to isoniazid

  • Retain activity against M(X)DR clinical isolates

  • Physicochemical properties akin to antitubercular drugs

Last year, Mycobacterium tuberculosis had the doubtful honor of being the top infectious killer worldwide. The current 6-month treatment, which was developed more than 30 years ago, has saved million of lives but bears the drawback of poor compliance; hence, the world needs a new shorter and safer TB treatment.

The biochemical screening of GSK compound library performed by Martinez et al. has identified new KatG-independent inhibitor of InhA active against M(X)DR Mtb strains, good drug-like properties, and in vivo activity similar to isoniazid overcoming the resistance and toxicological issues of the former drug.

Abstract

Despite being one of the first antitubercular agents identified, isoniazid (INH) is still the most prescribed drug for prophylaxis and tuberculosis (TB) treatment and, together with rifampicin, the pillars of current chemotherapy. A high percentage of isoniazid resistance is linked to mutations in the pro-drug activating enzyme KatG, so the discovery of direct inhibitors (DI) of the enoyl-ACP reductase (InhA) has been pursued by many groups leading to the identification of different enzyme inhibitors, active against Mycobacterium tuberculosis (Mtb), but with poor physicochemical properties to be considered as preclinical candidates. Here, we present a series of InhA DI active against multidrug (MDR) and extensively (XDR) drug-resistant clinical isolates as well as in TB murine models when orally dosed that can be a promising foundation for a future treatment.

Keywords

Tuberculosis
Antibiotic
InhA
Bactericidal
Drug discovery
Single-cell imaging
Catalase

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