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Infection and Immunity, October 2000, p. 5619-5627, Vol. 68, No. 10
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Gallium Disrupts Iron Metabolism of Mycobacteria Residing within Human Macrophages

Oyebode Olakanmi,1,2 Bradley E. Britigan,1,2 and Larry S. Schlesinger1,2,3,4,*

Division of Infectious Diseases, Department of Medicine,1 Departments of Microbiology3 and Veterans Affairs,2 and The Interdisciplinary Immunology Program,4 The University of Iowa College of Medicine, Iowa City, Iowa 52242

Received 6 January 2000/Returned for modification 18 February 2000/Accepted 29 June 2000

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 (Ga3+) to concentrate within mononuclear phagocytes and on evidence that Ga disrupts cellular Fe-dependent metabolic pathways by substituting for Fe3+ 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(NO3)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(NO3)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.

* Corresponding author. Mailing address: The University of Iowa, Department of Internal Medicine, 200 Hawkins Dr., SW54 GH, Iowa City, IA 52242. Phone: (319) 356-1387. Fax: (319) 356-4600. E-mail: larry-schlesinger{at}uiowa.edu.

Infection and Immunity, October 2000, p. 5619-5627, Vol. 68, No. 10
0019-9567/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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