Gallium disrupts iron metabolism of mycobacteria residing within human macrophages

Mycobacterium tuberculosis and M. avium complex (MAC) enter and multiply wi thin monocytes and macrophages in phagosomes. In vitro growth studies using standard culture media indicate that siderophoremediated iron (Fe) acquisi tion plays a critical role in the growth and metabolism of both M. tubercul osis and MAC. However, the applicability of such studies to conditions with in the macrophage phagosome is unclear, due in part to the absence of exper imental means to inhibit such a process. Based on the ability of gallium (G a3+) to concentrate within mononuclear phagocytes and on evidence that Ga d isrupts cellular Fe-dependent metabolic pathways by substituting for Fe3+ a nd 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,), and Ga-transferrin produce an Fe-reversible concentration-de pendent growth inhibition of M. tuberculosis strains and MAC grown extracel lularly and within human macrophages. Ga is bactericidal for M. tuberculosi s growing extracellularly and within macrophages. Finally, we provide evide nce that exogenonsly added Fe is acquired by intraphagosomal M. tuberculosi s and that Ga inhibits this Fe acquisition. Thus, Ga(NO,), disruption of my cobacterial Fe metabolism may serve as an experimental means to study the m echanism 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 Pe, this approach could have broad a pplicability to the study of Fe metabolism of other intracellular pathogens .