Arginine-deprivation-induced oxidative damage sterilizes Mycobacterium tuberculosis

Proceedings of the National Academy of Sciences of the United States of America
Sangeeta TiwariWilliam R Jacobs

Abstract

Reactive oxygen species (ROS)-mediated oxidative stress and DNA damage have recently been recognized as contributing to the efficacy of most bactericidal antibiotics, irrespective of their primary macromolecular targets. Inhibitors of targets involved in both combating oxidative stress as well as being required for in vivo survival may exhibit powerful synergistic action. This study demonstrates that the de novo arginine biosynthetic pathway in Mycobacterium tuberculosis (Mtb) is up-regulated in the early response to the oxidative stress-elevating agent isoniazid or vitamin C. Arginine deprivation rapidly sterilizes the Mtb de novo arginine biosynthesis pathway mutants ΔargB and ΔargF without the emergence of suppressor mutants in vitro as well as in vivo. Transcriptomic and flow cytometry studies of arginine-deprived Mtb have indicated accumulation of ROS and extensive DNA damage. Metabolomics studies following arginine deprivation have revealed that these cells experienced depletion of antioxidant thiols and accumulation of the upstream metabolite substrate of ArgB or ArgF enzymes. ΔargB and ΔargF were unable to scavenge host arginine and were quickly cleared from both immunocompetent and immunocompromised mice. In summary, o...Continue Reading

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Citations

Nov 14, 2019·Cellular and Molecular Life Sciences : CMLS·Qiyao ChaiCui Hua Liu
Jan 29, 2020·Annals of the New York Academy of Sciences·John Osei SekyerePetrus B Fourie
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Sep 8, 2018·Proceedings of the National Academy of Sciences of the United States of America·Valerie Mizrahi, Digby F Warner
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Oct 26, 2021·Frontiers in Microbiology·Nadeem JoudehDirk Linke
Dec 26, 2021·Nature Protocols·Jianbo FuFeng Zhu

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