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However, it is unknown how intracellular bacterial pathogens such as\n                    <jats:italic>Mtb<\/jats:italic>\n                    maintain respiration during infection despite the chemical effectors of host immunity.\n                    <jats:italic>Mtb<\/jats:italic>\n                    synthesizes diisonitrile lipopeptides that tightly chelate copper, but the role of these chalkophores in host-pathogen interactions is also unknown. We demonstrate that\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    chalkophores maintain the function of the heme-copper\n                    <jats:italic>\n                      bcc:aa\n                      <jats:sub>3<\/jats:sub>\n                    <\/jats:italic>\n                    respiratory supercomplex under copper limitation. Chalkophore deficiency impairs\n                    <jats:italic>Mtb<\/jats:italic>\n                    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.\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    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\n                    <jats:italic>Mtb<\/jats:italic>\n                    is independent of adaptive immunity and neutrophils. These data demonstrate that chalkophores counter host-inflicted copper deprivation and highlight a multilayered system by which\n                    <jats:italic>M. tuberculosis<\/jats:italic>\n                    maintains respiration during infection.\n                  <\/jats:p>","DOI":"10.7554\/elife.105794","type":"journal-article","created":{"date-parts":[[2025,2,20]],"date-time":"2025-02-20T09:25:06Z","timestamp":1740043506000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.105794","source":"Crossref","is-referenced-by-count":3,"title":["Chalkophore-mediated respiratory oxidase flexibility controls M. tuberculosis virulence"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8961-8672","authenticated-orcid":true,"given":"John A","family":"Buglino","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02yrq0923","id-type":"ROR","asserted-by":"publisher"}],"name":"Immunology Program, Sloan Kettering Institute","place":["New York, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3777-0546","authenticated-orcid":true,"given":"Yaprak","family":"Ozakman","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02yrq0923","id-type":"ROR","asserted-by":"publisher"}],"name":"Immunology Program, Sloan Kettering Institute","place":["New York, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"methodology","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6808-5117","authenticated-orcid":true,"given":"Chad E","family":"Hatch","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02yrq0923","id-type":"ROR","asserted-by":"publisher"}],"name":"Chemical Biology Program, Sloan Kettering Institute","place":["New York, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6159-6440","authenticated-orcid":true,"given":"Anna","family":"Benjamin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02yrq0923","id-type":"ROR","asserted-by":"publisher"}],"name":"Immunology Program, Sloan Kettering Institute","place":["New York, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"investigation","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7956-9659","authenticated-orcid":true,"given":"Derek S","family":"Tan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02yrq0923","id-type":"ROR","asserted-by":"publisher"}],"name":"Chemical Biology Program, Sloan Kettering Institute","place":["New York, United States"]},{"id":[{"id":"https:\/\/ror.org\/02yrq0923","id-type":"ROR","asserted-by":"publisher"}],"name":"Tri-Institutional Research Program, Memorial Sloan Kettering Cancer Center","place":["New York, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7918-5164","authenticated-orcid":true,"given":"Michael S","family":"Glickman","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02yrq0923","id-type":"ROR","asserted-by":"publisher"}],"name":"Immunology Program, Sloan Kettering Institute","place":["New York, United States"]}],"role":[{"role":"author","vocabulary":"crossref"},{"role":"corresponding-author","vocabulary":"crossref"},{"role":"conceptualization","vocabulary":"credit"},{"role":"investigation","vocabulary":"credit"},{"role":"supervision","vocabulary":"credit"},{"role":"writing-original-draft","vocabulary":"credit"},{"role":"writing-review-editing","vocabulary":"credit"}]}],"member":"4374","published-online":{"date-parts":[[2025,6,5]]},"reference":[{"key":"bib1","type":"software","article-title":"FastQC: a quality control tool for high throughput sequence data","volume-title":"Bioinformatics Babraham","author":"Andrews","year":"2010","unstructured":"Andrews S. 2010. 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