Intracellular peroxynitrite perturbs redox balance, bioenergetics, and Fe-S cluster homeostasis in Mycobacterium tuberculosis.

Autor: Dewan A; Department of Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, 560012, India., Jain C; Department of Chemistry, Indian Institute of Science Education and Research, Pune, 411008, India., Das M; Department of Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, 560012, India., Tripathi A; Department of Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, 560012, India., Sharma AK; Department of Chemistry, Indian Institute of Science Education and Research, Pune, 411008, India., Singh H; Department of Chemistry, Indian Institute of Science Education and Research, Pune, 411008, India., Malhotra N; National Center for Biological Sciences, Bengaluru, 560065, India., Seshasayee ASN; National Center for Biological Sciences, Bengaluru, 560065, India., Chakrapani H; Department of Chemistry, Indian Institute of Science Education and Research, Pune, 411008, India. Electronic address: harinath@iiserpune.ac.in., Singh A; Department of Microbiology and Cell Biology, Centre for Infectious Disease Research, Indian Institute of Science, Bengaluru, 560012, India. Electronic address: asingh@iisc.ac.in.
Jazyk: angličtina
Zdroj: Redox biology [Redox Biol] 2024 Sep; Vol. 75, pp. 103285. Date of Electronic Publication: 2024 Jul 31.
DOI: 10.1016/j.redox.2024.103285
Abstrakt: The ability of Mycobacterium tuberculosis (Mtb) to tolerate nitric oxide ( • NO) and superoxide (O 2 •- ) produced by phagocytes contributes to its success as a human pathogen. Recombination of • NO and O 2 •- generates peroxynitrite (ONOO - ), a potent oxidant produced inside activated macrophages causing lethality in diverse organisms. While the response of Mtb toward • NO and O 2 •- is well established, how Mtb responds to ONOO - remains unclear. Filling this knowledge gap is important to understand the persistence mechanisms of Mtb during infection. We synthesized a series of compounds that generate both • NO and O 2 •- , which should combine to produce ONOO - . From this library, we identified CJ067 that permeates Mtb to reliably enhance intracellular ONOO - levels. CJ067-exposed Mtb strains, including multidrug-resistant (MDR) and extensively drug-resistant (XDR) clinical isolates, exhibited dose-dependent, long-lasting oxidative stress and growth inhibition. In contrast, Mycobacterium smegmatis (Msm), a fast-growing, non-pathogenic mycobacterial species, maintained redox balance and growth in response to intracellular ONOO - . RNA-sequencing with Mtb revealed that CJ067 induces antioxidant machinery, sulphur metabolism, metal homeostasis, and a 4Fe-4S cluster repair pathway (suf operon). CJ067 impaired the activity of the 4Fe-4S cluster-containing TCA cycle enzyme, aconitase, and diminished bioenergetics of Mtb. Work with Mtb strains defective in SUF and IscS involved in Fe-S cluster biogenesis pathways showed that both systems cooperatively protect Mtb from intracellular ONOO - in vitro and inducible nitric oxide synthase (iNOS)-dependent growth inhibition during macrophage infection. Thus, Mtb is uniquely sensitive to intracellular ONOO - and targeting Fe-S cluster homeostasis is expected to promote iNOS-dependent host immunity against tuberculosis (TB).
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: