Unknown

Dataset Information

0

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


ABSTRACT: The ability of Mycobacterium tuberculosis (Mtb) to tolerate nitric oxide (NO) and superoxide (O2•-) produced by phagocytes contributes to its success as a human pathogen. Recombination of NO and O2•- generates peroxynitrite (ONOO-), a potent oxidant produced inside activated macrophages causing lethality in diverse organisms. While the response of Mtb toward NO and O2•- 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 O2•-, 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).

SUBMITTER: Dewan A 

PROVIDER: S-EPMC11369450 | biostudies-literature | 2024 Sep

REPOSITORIES: biostudies-literature

altmetric image

Publications

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

Dewan Arshiya A   Jain Charu C   Das Mayashree M   Tripathi Ashutosh A   Sharma Ajay Kumar AK   Singh Harshit H   Malhotra Nitish N   Seshasayee Aswin Sai Narain ASN   Chakrapani Harinath H   Singh Amit A  

Redox biology 20240731


The ability of Mycobacterium tuberculosis (Mtb) to tolerate nitric oxide (<sup>•</sup>NO) and superoxide (O<sub>2</sub><sup>•-</sup>) produced by phagocytes contributes to its success as a human pathogen. Recombination of <sup>•</sup>NO and O<sub>2</sub><sup>•-</sup> generates peroxynitrite (ONOO<sup>-</sup>), a potent oxidant produced inside activated macrophages causing lethality in diverse organisms. While the response of Mtb toward <sup>•</sup>NO and O<sub>2</sub><sup>•-</sup> is well establ  ...[more]

Similar Datasets

| S-EPMC8545095 | biostudies-literature
| S-EPMC8473347 | biostudies-literature
| S-EPMC3277930 | biostudies-literature
| S-EPMC8660018 | biostudies-literature
| S-EPMC5555796 | biostudies-literature
| S-EPMC8566947 | biostudies-literature
| S-EPMC9172572 | biostudies-literature
| S-EPMC9841358 | biostudies-literature
| S-EPMC7064780 | biostudies-literature
| S-EPMC6912456 | biostudies-literature