Chalkophore mediated respiratory oxidase flexibility controls M. tuberculosis virulence.

Oxidative phosphorylation has emerged as a critical therapeutic vulnerability of M. tuberculosis, but it is unknown how M. tuberculosis and other pathogens maintain respiration during infection. M. tuberculosis synthesizes diisonitrile lipopeptide chalkophores that chelate copper tightly, but their role in host-pathogen interactions is also unknown. We demonstrate that M. tuberculosis chalkophores maintain the function of the heme-copper bcc:aa3 respiratory oxidase under copper limitation. Chalkophore deficient M. tuberculosis cannot survive, respire to oxygen, or produce ATP under copper deprivation in culture. M. tuberculosis lacking chalkophore biosynthesis is attenuated in mice, a phenotype that is severely exacerbated by loss of the CytBD alternative respiratory oxidase (encoded by cydAB), 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 in M. tuberculosis.