title: Resistance mechanisms of Mycobacterium tuberculosis against phagosomal copper overload.
abstract: Mycobacterium tuberculosis is an important bacterial pathogen with an extremely slow growth rate, an unusual outer membrane of very low permeability and a cunning ability to survive inside the human host despite a potent immune response. A key trait of M. tuberculosis is to acquire essential nutrients while still preserving its natural resistance to toxic compounds. In this regard, copper homeostasis mechanisms are particularly interesting, because copper is an important element for bacterial growth, but copper overload is toxic. In M. tuberculosis at least two enzymes require copper as a cofactor: the Cu/Zn-superoxide dismutase SodC and the cytochrome c oxidase which is essential for growth in vitro. Mutants of M. tuberculosis lacking the copper metallothionein MymT, the efflux pump CtpV and the membrane protein MctB are more susceptible to copper indicating that these proteins are part of a multipronged system to balance intracellular copper levels. Recent evidence showed that part of copper toxicity is a reversible damage of Fe-S clusters of dehydratases and the displacement of other divalent cations such as zinc and manganese as cofactors in proteins. There is accumulating evidence that macrophages use copper to poison bacteria trapped inside phagosomes. Here, we review the rapidly increasing knowledge about copper homeostasis in M. tuberculosis and contrast those with similar mechanisms in Escherichia coli. These findings reveal an intricate interplay between the host which aims to overload the phagosome with copper and M. tuberculosis which utilizes several mechanisms to reduce the toxic effects of excess copper.
authors.affiliation: Department of Microbiology, University of Alabama at Birmingham, 609 Bevill Biomedical Research Building, 845 19th Street South, Birmingham, AL 35294, USA.
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Rowland
authors.forename: Michael
authors.initials: M
authors.lastname: Niederweis
mesh_terms: D003300:Copper / Q000276:immunology / Q000378:metabolism* / Q000502:physiology / Q000633:toxicity; D004926:Escherichia coli / Q000378:metabolism; D006706:Homeostasis / Q000502:physiology; D006801:Humans; D008264:Macrophages / Q000378:metabolism / Q000382:microbiology; D009169:Mycobacterium tuberculosis / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity; D010588:Phagosomes / Q000378:metabolism*; D014774:Virulence
chemical_list: D003300:Copper