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

Martínez-Hoyos, María; Pérez-Herrán, Esther; Gulten, Gulcin; Encinas, Lourdes; Álvarez-Gómez, Daniel; Álvarez, Emilio; Ferrer-Bazaga, Santiago; García-Pérez, Adolfo; Ortega, Fátima; Angulo-Barturen, Íñigo; Rullas-Trincado, Joaquin; Ruano, Delia Blanco; Tôrres, Pedro; Castañeda, Pablo; Huss, Sophie; Menéndez, Roberto; Valle, Silvia González del; Ballell, Lluís; Barros, David; Modha, Sundip; Dhar, Neeraj; Signorino-Gelo, François; McKinney, John D.; Garcia-Bustos, Jose; Lavandera, José Luís; Sacchettini, James C.; Jiménez, María Soledad; Martín-Casabona, N; Castro-Pichel, Julia; Mendoza-Losana, Alfonso

doi:10.1016/j.ebiom.2016.05.006

Cited by 65 publications

(63 citation statements)

References 49 publications

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“…G205 and A206 are in close proximity to residues I202, V203 and L207 which interact with direct InhA inhibitors (12). The majority of the mutations we identified are novel, except S94, D148 and M161 which are known to provide resistance against NITD-916, and M103 which confers resistance to GSK693 (3; 5). These results highlight the overlapping binding sites of different InhA inhibitors.…”

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confidence: 99%

“…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).…”

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confidence: 99%

“…M103 and I215 are active site residues, whilst I21 and F41 play a role in stabilizing NADH with which NITD-916 forms a ternary complex (10; 11). M103 and I215 interact with NITD-916 (5), whilst M161 and I202 form interactions with GSK625 and PT70 (3; 4). R195 is in close proximity to the active site residues G192 and G193, and Q214 is close to I215 (5).…”

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

et al. 2017

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“…Perhaps KatG fails to activate isoniazid under nonreplicating conditions. To test this hypothesis, InhA inhibitors that do not require KatG activation could be tested against nonreplicating bacilli (182). Another possibility is that compound 8 , like isoniazid itself, may have more than one target, but unlike isoniazid, one of the alternate targets of compound 8 may be essential in hypoxia.…”

Section: Class II Persisters: a Majority Population Of Nonreplicatmentioning

confidence: 99%

Targeting Phenotypically TolerantMycobacterium tuberculosis

2017

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While the immune system is credited with averting tuberculosis in billions of individuals exposed to Mycobacterium tuberculosis, the immune system is also culpable for tempering the ability of antibiotics to deliver swift and durable cure of disease. In individuals afflicted with tuberculosis, host immunity produces diverse microenvironmental niches that support suboptimal growth, or complete growth arrest, of M. tuberculosis. The physiological state of nonreplication in bacteria is associated with phenotypic drug tolerance. Many of these host microenvironments, when modeled in vitro by carbon starvation, complete nutrient starvation, stationary phase, acidic pH, reactive nitrogen intermediates, hypoxia, biofilms, and withholding streptomycin from the streptomycin-addicted strain SS18b, render M. tuberculosis profoundly tolerant to many of the antibiotics that are given to tuberculosis patients in a clinical setting. Targeting nonreplicating persisters is anticipated to reduce the duration of antibiotic treatment and rate of post-treatment relapse. Some promising drugs to treat tuberculosis, such as rifampicin and bedaquiline, only kill nonreplicating M. tuberculosis in vitro at concentrations far greater than their minimal inhibitory concentrations against replicating bacilli. There is an urgent demand to identify which of the currently used antibiotics, and which of the molecules in academic and corporate screening collections, have potent bactericidal action on nonreplicating M. tuberculosis. With this goal, we review methods of high throughput screening to target nonreplicating M. tuberculosis and methods to progress candidate molecules. A classification based on structures and putative targets of molecules that have been reported to kill nonreplicating M. tuberculosis revealed a rich diversity in pharmacophores. However, few of these compounds were tested under conditions that would exclude the impact of adsorbed compound acting during the recovery phase of the assay, and few were tested under more than one condition imposing nonreplication. That nonreplicating mycobacteria are metabolically active was corroborated by their susceptibility to several antibiotics and tool compounds that target the synthesis of lipids, RNA, DNA, proteins, and peptidoglycan.

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“…Introducing the amide FG results in movement of the phenyl group of 9 to allow an additional H‐bond interaction with Met98 backbone CO (Figure C). Similarly, as a result of the deconstructed fragment 34 retaining the binding pose of 45 (pIC 50 =8.1) as well as occupying the same pyrazole binding pocket as fragment 9 , compound 47 (Figure and Scheme S5) was synthesized. 47 showed good InhA activity (pIC 50 =7.3) and maintained the pose relative to 45 (Figure S7).…”

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Screening of a Novel Fragment Library with Functional Complexity against Mycobacterium tuberculosis InhA

et al. 2018

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Our findings reported herein provide support for the benefits of including functional group complexity (FGC) within fragments when screening against protein targets such as Mycobacterium tuberculosis InhA. We show that InhA fragment actives with FGC maintained their binding pose during elaboration. Furthermore, weak fragment hits with functional group handles also allowed for facile fragment elaboration to afford novel and potent InhA inhibitors with good ligand efficiency metrics for optimization.

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

Cited by 65 publications

References 49 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

Targeting Phenotypically TolerantMycobacterium tuberculosis

Screening of a Novel Fragment Library with Functional Complexity against Mycobacterium tuberculosis InhA

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