Chalkophore mediated respiratory oxidase flexibility controlsM. tuberculosisvirulence

Oxidative phosphorylation has emerged as a critical therapeutic vulnerability ofM. tuberculosis, but it is unknown howM. tuberculosisand other pathogens maintain respiration during infection.M. tuberculosissynthesizes diisonitrile lipopeptide chalkophores that chelate copper tightly, but their role in host-pathogen interactions is also unknown. We demonstrate thatM. tuberculosischalkophores maintain the function of the heme-copperbcc:aa₃respiratory oxidase under copper limitation. Chalkophore deficientM. tuberculosiscannot survive, respire to oxygen, or produce ATP under copper deprivation in culture.M. tuberculosislacking chalkophore biosynthesis is attenuated in mice, a phenotype that is severely exacerbated by loss of the CytBD alternative respiratory oxidase (encoded bycydAB), revealing a multilayered flexibility of the respiratory chain that maintains oxidative phosphorylation during infection. Taken together, these data demonstrate that chalkophores counter host inflicted copper deprivation and highlight that protection of cellular respiration is a critical virulence function inM. tuberculosis.