Gallium Nitrate Is Efficacious in Murine Models of Tuberculosis and Inhibits Key Bacterial Fe-Dependent Enzymes

Abstract

ABSTRACTAcquiring iron (Fe) is critical to the metabolism and growth ofMycobacterium tuberculosis. Disruption of Fe metabolism is a potential approach for novel antituberculous therapy. Gallium (Ga) has many similarities to Fe. Biological systems are often unable to distinguish Ga3+from Fe3+. Unlike Fe3+, Ga3+cannot be physiologically reduced to Ga2+. Thus, substituting Ga for Fe in the active site of enzymes may render them nonfunctional. We previously showed that Ga inhibits growth ofM. tuberculosisin broth and within cultured human macrophages. We now report that Ga(NO3)3shows efficacy in murine tuberculosis models. BALB/c SCID mice were infected intratracheally withM. tuberculosis, following which they received daily intraperitoneal saline, Ga(NO3)3, or NaNO3. All mice receiving saline or NaNO3died. All Ga(NO3)3-treated mice survived.M. tuberculosisCFU in the lungs, liver, and spleen of the NaNO3-treated or saline-treated mice were significantly higher than those in Ga-treated mice. When BALB/c mice were substituted for BALB/c SCID mice as a chronic (nonlethal) infection model, Ga(NO3)3treatment significantly decreased lung CFU. To assess the mechanism(s) whereby Ga inhibits bacterial growth, the effect of Ga onM. tuberculosisribonucleotide reductase (RR) (a key enzyme in DNA replication) and aconitase activities was assessed. Ga decreasedM. tuberculosisRR activity by 50 to 60%, but no additional decrease in RR activity was seen at Ga concentrations that completely inhibited mycobacterial growth. Ga decreased aconitase activity by 90%. Ga(NO3)3shows efficacy in murineM. tuberculosisinfection and leads to a decrease in activity of Fe-dependent enzymes. Additional work is warranted to further define Ga's mechanism of action and to optimize delivery forms for possible therapeutic uses in humans.