Isoniazid bactericidal activity involves electron transport chain perturbation

Sheng Zeng, Karine Soetaert, Faustine Ravon, Marie Vandeput, Dirk Bald, Jean Michel Kauffmann, Vanessa Mathys, Ruddy Wattiez, Véronique Fontaine

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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 bc 1 and F o F 1 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 bc 1 , and F o F 1 ATP synthase in INH’s bactericidal activity and pinpoints the participation of the cytochrome bd oxidase in protection against this drug under stress conditions.

LanguageEnglish
Article numbere01841-18
JournalAntimicrobial Agents and Chemotherapy
DOIs
Publication statusPublished - 1 Mar 2019

Fingerprint

Isoniazid
Electron Transport
Adenosine Triphosphate
Electron Transport Complex IV
NADH Dehydrogenase
Succinate Dehydrogenase
Cytochromes
Mycobacterium bovis
bedaquiline
Mycolic Acids
Pharmaceutical Preparations
Acetylcysteine
Starvation
Oxygen Consumption
Membrane Potentials
Antioxidants
Anti-Bacterial Agents

Keywords

  • Bedaquiline
  • Electron transport chain
  • Isoniazid
  • Mycobacterium tuberculosis
  • Persistence
  • Q203

Cite this

Zeng, S., Soetaert, K., Ravon, F., Vandeput, M., Bald, D., Kauffmann, J. M., ... Fontaine, V. (2019). Isoniazid bactericidal activity involves electron transport chain perturbation. Antimicrobial Agents and Chemotherapy, [e01841-18]. https://doi.org/10.1128/AAC.01841-18
Zeng, Sheng ; Soetaert, Karine ; Ravon, Faustine ; Vandeput, Marie ; Bald, Dirk ; Kauffmann, Jean Michel ; Mathys, Vanessa ; Wattiez, Ruddy ; Fontaine, Véronique. / Isoniazid bactericidal activity involves electron transport chain perturbation. In: Antimicrobial Agents and Chemotherapy. 2019.
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Zeng, S, Soetaert, K, Ravon, F, Vandeput, M, Bald, D, Kauffmann, JM, Mathys, V, Wattiez, R & Fontaine, V 2019, 'Isoniazid bactericidal activity involves electron transport chain perturbation', Antimicrobial Agents and Chemotherapy. https://doi.org/10.1128/AAC.01841-18

Isoniazid bactericidal activity involves electron transport chain perturbation. / Zeng, Sheng; Soetaert, Karine; Ravon, Faustine; Vandeput, Marie; Bald, Dirk; Kauffmann, Jean Michel; Mathys, Vanessa; Wattiez, Ruddy; Fontaine, Véronique.

In: Antimicrobial Agents and Chemotherapy, 01.03.2019.

Research output: Contribution to JournalArticleAcademicpeer-review

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T1 - Isoniazid bactericidal activity involves electron transport chain perturbation

AU - Zeng, Sheng

AU - Soetaert, Karine

AU - Ravon, Faustine

AU - Vandeput, Marie

AU - Bald, Dirk

AU - Kauffmann, Jean Michel

AU - Mathys, Vanessa

AU - Wattiez, Ruddy

AU - Fontaine, Véronique

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N2 - 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 bc 1 and F o F 1 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 bc 1 , and F o F 1 ATP synthase in INH’s bactericidal activity and pinpoints the participation of the cytochrome bd oxidase in protection against this drug under stress conditions.

AB - 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 bc 1 and F o F 1 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 bc 1 , and F o F 1 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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