The anti-mycobacterial activity of the cytochrome bcc inhibitor Q203 can be enhanced by small-molecule inhibition of cytochrome bd

Lü, Ping; Asseri, Amer H.; Kremer, M; Maaskant, Janneke J.; Ummels, Roy; Lill, Holger; Bald, Dirk

doi:10.1038/s41598-018-20989-8

Cited by 69 publications

(74 citation statements)

References 48 publications

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“…To test this hypothesis, the cytochrome bd inhibitor aurachin D was used (Fig. 7A) (47,48). We noted that this inhibitor was not bactericidal to M. bovis BCG (data not shown), as reported for M. tuberculosis (47).…”

Section: Resultsmentioning

confidence: 81%

Isoniazid Bactericidal Activity Involves Electron Transport Chain Perturbation

Zeng

Soetaert

Ravon

et al. 2019

Antimicrob Agents Chemother

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Accumulating evidence suggests that the bactericidal activity of some antibiotics may not be directly initiated by target inhibition. The activity of isoniazid (INH), a key first-line bactericidal antituberculosis drug currently known to inhibit mycolic acid synthesis, becomes extremely poor under stress conditions, such as hypoxia and starvation. This suggests that the target inhibition may not fully explain the bactericidal activity of the drug. Here, we report that INH rapidly increased Mycobacterium bovis BCG cellular ATP levels and enhanced oxygen consumption. The INH-triggered ATP increase and bactericidal activity were strongly compromised by Q203 and bedaquiline, which inhibit mycobacterial cytochrome bc1 and FoF1 ATP synthase, respectively. Moreover, the antioxidant N-acetylcysteine (NAC) but not 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPOL) abrogated the INH-triggered ATP increase and killing. These results reveal a link between the energetic (ATP) perturbation and INH’s killing. Furthermore, the INH-induced energetic perturbation and killing were also abrogated by chemical inhibition of NADH dehydrogenases (NDHs) and succinate dehydrogenases (SDHs), linking INH’s bactericidal activity further to the electron transport chain (ETC) perturbation. This notion was also supported by the observation that INH dissipated mycobacterial membrane potential. Importantly, inhibition of cytochrome bd oxidase significantly reduced cell recovery during INH challenge in a culture settling model, suggesting that the respiratory reprogramming to the cytochrome bd oxidase contributes to the escape of INH killing. This study implicates mycobacterial ETC perturbation through NDHs, SDHs, cytochrome bc1, and FoF1 ATP synthase in INH’s bactericidal activity and pinpoints the participation of the cytochrome bd oxidase in protection against this drug under stress conditions.

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Section: Resultsmentioning

confidence: 81%

Isoniazid Bactericidal Activity Involves Electron Transport Chain Perturbation

Zeng

Soetaert

Ravon

et al. 2019

Antimicrob Agents Chemother

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“…5C), thus suggesting that Q203 would also have a similar binding mechanism and a similar effect on the activity of M. smegmatis CIII. Indeed, recent studies of the antimycobacterial activity of Q203 on M. tuberculosis and M. smegmatis demonstrated that Q203 targets the bcc complex in both with similar affinity (42). We investigated the in vitro inhibition of M. smegmatis SC III-IV by Q203 by means of the menadiol/oxygen oxidoreductase activity assay and compared the effect with a hybrid supercomplex of M. tuberculosis bcc-CIII and M. smegmatis aa 3 -CIV.…”

Section: Quinone and Quinone Binding Pocketsmentioning

confidence: 99%

An electron transfer path connects subunits of a mycobacterial respiratory supercomplex

Gong

et al. 2018

Science

146

217

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We report a 3.5-angstrom-resolution cryo–electron microscopy structure of a respiratory supercomplex isolated fromMycobacterium smegmatis.It comprises a complex III dimer flanked on either side by individual complex IV subunits. Complex III and IV associate so that electrons can be transferred from quinol in complex III to the oxygen reduction center in complex IV by way of a bridging cytochrome subunit. We observed a superoxide dismutase-like subunit at the periplasmic face, which may be responsible for detoxification of superoxide formed by complex III. The structure reveals features of an established drug target and provides a foundation for the development of treatments for human tuberculosis.

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“…Recent literature has shown that other QcrB inhibitors (namely, Q203 and TB47) have better efficacy within the acute model of TB infection and when used in combination with first line drugs such as rifampicin and pyrazinamide [30]. Due to the respiratory flexibility of Mtb there have been many reports that the efficacy of QcrB inhibitors might be greatly enhanced by tandem inhibition of the cytochrome bd oxidase based upon in vitro data [21,22,[43][44][45]. However, this dual inhibition concept was strengthened by the impressive in vivo efficacy observed when QcrB inhibitors were evaluated against Mycobacterium ulcerans, a disease-causing strain which lacking cyt-bd oxidase [46][47][48].…”

Section: Resultsmentioning

confidence: 99%

Intracellular and in vivo evaluation of imidazo[2,1-b]thiazole-5-carboxamide anti-tuberculosis compounds

et al. 2020

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The imidazo[2,1-b]thiazole-5-carboxamides (ITAs) are a promising class of anti-tuberculosis agents shown to have potent activity in vitro and to target QcrB, a key component of the mycobacterial cytochrome bcc-aa3 super complex critical for the electron transport chain. Herein we report the intracellular macrophage potency of nine diverse ITA analogs with MIC values ranging from 0.0625-2.5 μM and mono-drug resistant potency ranging from 0.0017 to 7 μM. The in vitro ADME properties (protein binding, CaCo-2, human microsomal stability and CYP450 inhibition) were determined for an outstanding compound of the series, ND-11543. ND-11543 was tolerable at >500 mg/kg in mice and at a dose of 200 mg/kg displayed good drug exposure in mice with an AUC(0-24h) >11,700 ng�hr/mL and a >24 hr half-life. Consistent with the phenotype observed with other QcrB inhibitors, compound ND-11543 showed efficacy in a chronic murine TB infection model when dosed at 200 mg/kg for 4 weeks. The efficacy was not dependent upon exposure, as pre-treatment with a known CYP450-inhibitor did not substantially improve efficacy. The ITAs are an interesting scaffold for the development of new anti-TB drugs especially in combination therapy based on their favorable properties and novel mechanism of action.

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The anti-mycobacterial activity of the cytochrome bcc inhibitor Q203 can be enhanced by small-molecule inhibition of cytochrome bd

Cited by 69 publications

References 48 publications

Isoniazid Bactericidal Activity Involves Electron Transport Chain Perturbation

Isoniazid Bactericidal Activity Involves Electron Transport Chain Perturbation

An electron transfer path connects subunits of a mycobacterial respiratory supercomplex

Intracellular and in vivo evaluation of imidazo[2,1-b]thiazole-5-carboxamide anti-tuberculosis compounds

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