Gallium disrupts iron metabolism of mycobacteria residing within human macrophages.
Mycobacterium tuberculosis and M. avium complex (MAC) enter and multiply within monocytes and macrophages in phagosomes. In vitro growth studies using standard culture media indicate that siderophore-mediated iron (Fe) acquisition plays a critical role in the growth and metabolism of both M. tuberculosis and MAC. However, the applicability of such studies to conditions within the macrophage phagosome is unclear, due in part to the absence of experimental means to inhibit such a process. Based on the ability of gallium (Ga(3+)) to concentrate within mononuclear phagocytes and on evidence that Ga disrupts cellular Fe-dependent metabolic pathways by substituting for Fe(3+) and failing to undergo redox cycling, we hypothesized that Ga could disrupt Fe acquisition and Fe-dependent metabolic pathways of mycobacteria. We find that Ga(NO(3))(3) and Ga-transferrin produce an Fe-reversible concentration-dependent growth inhibition of M. tuberculosis strains and MAC grown extracellularly and within human macrophages. Ga is bactericidal for M. tuberculosis growing extracellularly and within macrophages. Finally, we provide evidence that exogenously added Fe is acquired by intraphagosomal M. tuberculosis and that Ga inhibits this Fe acquisition. Thus, Ga(NO(3))(3) disruption of mycobacterial Fe metabolism may serve as an experimental means to study the mechanism of Fe acquisition by intracellular mycobacteria and the role of Fe in intracellular survival. Furthermore, given the inability of biological systems to discriminate between Ga and Fe, this approach could have broad applicability to the study of Fe metabolism of other intracellular pathogens.
Olakanmi
O
O
Division of Infectious Diseases, Department of Medicine, The University of Iowa College of Medicine, Iowa City, Iowa 52242, USA.
Britigan
B E
BE
Schlesinger
L S
LS
D002478:Cells, Cultured; D003470:Culture Media; D005708:Gallium / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007501:Iron / Q000378:metabolism*; D008264:Macrophages / Q000382:microbiology*; D016676:Macrophages, Alveolar / Q000382:microbiology; D008855:Microscopy, Electron, Scanning; D009000:Monocytes / Q000166:cytology; D015269:Mycobacterium avium Complex / Q000254:growth & development / Q000378:metabolism; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D014168:Transferrin / Q000378:metabolism
D003470:Culture Media; D014168:Transferrin; D005708:Gallium; D007501:Iron; C027235:gallium nitrate