Chalkophore-mediated respiratory oxidase flexibility controls M. tuberculosis virulence Journal Article
| Authors: | Buglino, J. A.; Ozakman, Y.; Hatch, C. E.; Benjamin, A.; Tan, D. S.; Glickman, M. S. |
| Article Title: | Chalkophore-mediated respiratory oxidase flexibility controls M. tuberculosis virulence |
| Abstract: | Oxidative phosphorylation has emerged as a critical therapeutic vulnerability of M. tuberculosis (Mtb). However, it is unknown how intracellular bacterial pathogens such as Mtb maintain respiration during infection despite the chemical effectors of host immunity. Mtb synthesizes diisonitrile lipopeptides that tightly chelate copper, but the role of these chalkophores in host-pathogen interactions is also unknown. We demonstrate that M. tuberculosis chalkophores maintain the function of the heme-copper bcc:aa3 respiratory supercomplex under copper limitation. Chalkophore deficiency impairs Mtb survival, respiration to oxygen, and ATP production under copper deprivation in culture, effects that are exacerbated by loss of the heme-dependent Cytochrome BD respiratory oxidase. Our genetic analyses indicate that the maintenance of respiration is the major cellular target of chalkophore-mediated copper acquisition. M. tuberculosis lacking chalkophore biosynthesis is attenuated in mice, a phenotype that is also severely exacerbated by loss of the CytBD respiratory oxidase. We find that the host immune pressure that attenuates chalkophore-deficient Mtb is independent of adaptive immunity and neutrophils. These data demonstrate that chalkophores counter host-inflicted copper deprivation and highlight a multilayered system by which M. tuberculosis maintains respiration during infection. |
| Keywords: | oxidative phosphorylation; copper; tuberculosis; resistance; mycobacterium-tuberculosis; acquisition; m. tuberculosis; nutrional immunity; supercomplex |
| Journal Title: | eLife |
| Volume: | 14 |
| ISSN: | 2050-084X |
| Publisher: | eLife Sciences Publications Ltd. |
| Date Published: | 2025-06-05 |
| Start Page: | RP105794 |
| Language: | English |
| ACCESSION: | WOS:001503950800001 |
| DOI: | 10.7554/eLife.105794 |
| PROVIDER: | wos |
| PMCID: | PMC12140626 |
| PUBMED: | 40472191 |
| Notes: | Article -- MSK Cancer Center Support Grant (P30 CA008748) acknowledged in PubMed and PDF -- MSK corresponding author is Michael Glickman -- Source: Wos |
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