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Abstract
Pathogenic mycobacteria require copper to survive within their host. As this essential mineral is toxic in abundance, both pathogen and host have evolved mechanisms to control levels of free copper ions. Nutritional immunity refers to host processes to restrict availability of copper and other trace metals in some niches while greatly increasing their concentrations in others to defend against invading microbes. How the human pathogen Mycobacterium tuberculosis acquires copper from its host has not been elucidated. Herein, we demonstrate that a nonribosomal peptide synthase (NRPS) operon conserved in this agent of tuberculosis and in the related fish pathogen Mycobacterium marinum is required for scavenging copper from low-copper environments through production of copper-binding chalkophores. Outer membrane protein PPE1 encoded in the same operon and required for copper scavenging is not involved in export of chalkophores to the surface, which suggests function in import of copper-chalkophore adducts. Cytoplasmic membrane P-type ATPase CtpB is also required for growth in low-copper environments, but a M. tuberculosis CtpB null strain is hypervirulent in mouse infection studies, in contrast to NRPS operon mutants which are highly attenuated. CtpB is herein proposed to export copper to the periplasm for production of copper-dependent respiration complexes required for growth and energy generation by these obligate aerobic bacteria. This work identifies important copper trafficking processes that enable pathogenic intracellular mycobacteria to counters host copper nutritional immunity mechanisms.