2-Aryl benzazole derived new class of anti-tubercular compounds: Endowed to eradicate mycobacterium tuberculosis in replicating and non-replicating forms

Velappan, Anand Babu; Datta, Dhrubajyoti; Ma, Rui; Rana, Shiwani; Ghosh, Kalyan Sundar; Hari, Natarajan; Franzblau, Scott G.; Debnath, Joy

doi:10.1016/j.bioorg.2020.104170

Cited by 6 publications

(3 citation statements)

References 46 publications

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“…In M. tuberculosis , DMK is a precursor in MK biosynthesis. Interestingly, small molecule inhibitors of MenG, the enzyme that converts DMK into MK, were bactericidal in M. tuberculosis 33,44 . This substantiates the inability of Mtbd to turn over DMK and highlights the tight redox control between the quinone pool and Mtbd .…”

Section: Discussionmentioning

confidence: 99%

“…Mtbd is characterized by a unique disulfide bond that was hypothesized to reduce the flexibility of the substrate binding Q-loop (Fig 5A ) and thereby confer a regulatory role for enzyme activity 12,33 . Previous studies faced limitations examining this mechanism, as they relied on chemical reductants such as DTT to reduce the quinone pool, which inadvertently affects the disulfide bond itself.…”

Section: Mtbd Activity Is Regulated By a Unique Q-loop Disulfide Bondmentioning

confidence: 99%

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Menaquinone-specific oxidation byM. tuberculosiscytochromebdis redox regulated by the Q-loop disulfide bond

van der Velden,

Waterham,

Jeuken

2024

Preprint

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CytochromebdfromMycobacterium tuberculosis(Mtbd) is a menaquinol oxidase that has gained considerable interest as an antibiotic target due to its importance in survival under infectious conditions.Mtbdcontains a characteristic disulfide bond that has been hypothesized to confer a redox regulatory role during infection by constraining the movement of the menaquinone-binding Q-loop. Interference of reductants used in the standard activity assay of quinol oxidases has prevented testing of this hypothesis. Here, the role of the disulfide bond and quinone specificity ofMtbdhas been determined by the reconstitution of a minimal respiratory chain consisting of a NADH dehydrogenase andMtbd, both in detergent and native-like lipid environments. Comparison to cytochromebdfromEscherichia coli(Ecbd) confirms thatMtbdis under tight redox regulation and is selective for menaquinol, unable to oxidize either ubiquinol or demethylmenaquinol. Reduction of theMtbddisulfide bond resulted in a decrease in oxidase activity up to 90%, depending on menaquinol concentrations. In addition, the catalytic rates ofEcbdandMtbdare over 10 times lower with the natural lipophilic quinones in comparison to their often-used hydrophilic analogs. Additionally, unlikeEcbd, the activity ofMtbdis substrate inhibited at physiologically relevant menaquinol concentrations. We signifyMtbdas the first redox sensory terminal oxidase and propose that this enablesMtbdto adapt its activity in defence against reactive oxygen species encountered during infection byM. tuberculosis.

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Section: Discussionmentioning

confidence: 99%

Section: Mtbd Activity Is Regulated By a Unique Q-loop Disulfide Bondmentioning

confidence: 99%

Menaquinone-specific oxidation byM. tuberculosiscytochromebdis redox regulated by the Q-loop disulfide bond

van der Velden,

Waterham,

Jeuken

2024

Preprint

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“…Velappan and co-workers synthesized 2-aryl benzothiazole based dual targeted compounds 118a–d , 120a , 123a–d through the reaction of 2-amino thio phenol 1 with various heterocyclic derivatives (Scheme 32, Table 26). 69…”

Section: Recent Synthesis Of Benzothiazole Based Anti-tubercular Mole...mentioning

confidence: 99%

Recent advances in the synthesis of new benzothiazole based anti-tubercular compounds

et al. 2023

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Mycobacterial FtsZ and inhibitors: a promising target for the anti-tubercular drug development

Shinde,

Pathan,

Chinnam

et al. 2023

Mol Divers

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2-Aryl benzazole derived new class of anti-tubercular compounds: Endowed to eradicate mycobacterium tuberculosis in replicating and non-replicating forms

Cited by 6 publications

References 46 publications

Menaquinone-specific oxidation byM. tuberculosiscytochromebdis redox regulated by the Q-loop disulfide bond

Menaquinone-specific oxidation byM. tuberculosiscytochromebdis redox regulated by the Q-loop disulfide bond

Recent advances in the synthesis of new benzothiazole based anti-tubercular compounds

Mycobacterial FtsZ and inhibitors: a promising target for the anti-tubercular drug development

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