Mycobacterial Cell Wall Synthesis Inhibitors Cause Lethal ATP Burst

Frontiers in Microbiology
Annanya Shetty, Thomas Dick

Abstract

Mycobacterial cell wall inhibitors interfere with targets involved in synthesis of mycolic acids, arabinogalactan and peptidoglycan. These antibiotics corrupt structural integrity of the cell envelope and this is believed to be the cause of drug mediated cell death. Here, we show that treatment of Mycobacterium bovis BCG with these mechanistically different classes of cell wall inhibitors at MIC caused a 4 to 5-fold increase in intrabacterial ATP concentration. This effect on ATP homeostasis was specific to inhibitors of cell wall synthesis and not observed for other anti-tuberculosis drugs. Treating M. bovis BCG with sub-MIC concentrations of the ATP synthase inhibitor bedaquiline or the uncoupler carbonyl cyanide 3-chlorophenylhydrazone suppressed drug induced ATP surge, suggesting that the increase in ATP concentration was due to increased oxidative phosphorylation. Pharmacological suppression of the ATP burst attenuated bactericidal activity of the cell wall-targeting drugs up to 100-fold, suggesting that increased ATP levels are associated with the lethal effect of these antibiotics. Interestingly, inhibition of the ATP burst also suppressed induction of the promoter of the cell envelope stress response operon iniBAC by ce...Continue Reading

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Citations

Jan 16, 2019·Antimicrobial Agents and Chemotherapy·Sheng ZengVéronique Fontaine
Jun 12, 2019·FEMS Microbiology Reviews·Arundhati MaitraSanjib Bhakta
Jun 12, 2019·Antimicrobial Agents and Chemotherapy·Marissa Lindman, Thomas Dick
Jul 8, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Morgan MaioliniRahul R Deshmukh
Jul 19, 2020·Proceedings of the National Academy of Sciences of the United States of America·Trever C SmithBree B Aldridge
Jul 4, 2019·MBio·Diego A Vargas-BlancoScarlet S Shell
Jun 28, 2019·Frontiers in Microbiology·Sheng ZengVéronique Fontaine
Nov 19, 2019·Progress in Biophysics and Molecular Biology·Ludovica Mascolo, Dirk Bald
Jan 29, 2021·Frontiers in Cellular and Infection Microbiology·Erik J HasenoehrlMichael Berney
Apr 4, 2021·International Journal of Molecular Sciences·Christina CahillJames J Phelan
Jun 12, 2021·Tuberculosis·Pooja HegdeCourtney C Aldrich

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Methods Mentioned

BETA
Assay
Fluorescence

Software Mentioned

Graph Pad Prism

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