Gallium nitrate is efficacious in murine models of tuberculosis and inhibits key bacterial Fe-dependent enzymes.
Acquiring iron (Fe) is critical to the metabolism and growth of Mycobacterium 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 Ga(3+) from Fe(3+). Unlike Fe(3+), Ga(3+) cannot be physiologically reduced to Ga(2+). Thus, substituting Ga for Fe in the active site of enzymes may render them nonfunctional. We previously showed that Ga inhibits growth of M. tuberculosis in broth and within cultured human macrophages. We now report that Ga(NO3)3 shows efficacy in murine tuberculosis models. BALB/c SCID mice were infected intratracheally with M. tuberculosis, following which they received daily intraperitoneal saline, Ga(NO3)3, or NaNO3. All mice receiving saline or NaNO3 died. All Ga(NO3)3-treated mice survived. M. tuberculosis CFU 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)3 treatment significantly decreased lung CFU. To assess the mechanism(s) whereby Ga inhibits bacterial growth, the effect of Ga on M. tuberculosis ribonucleotide reductase (RR) (a key enzyme in DNA replication) and aconitase activities was assessed. Ga decreased M. tuberculosis RR 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)3 shows efficacy in murine M. tuberculosis infection 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.
Medical and Research Services, VA Medical Center-Cincinnati, Cincinnati, Ohio, USA.
Oyebode
O
Olakanmi
Banurekha
B
Kesavalu
Rajamouli
R
Pasula
Maher Y
MY
Abdalla
Larry S
LS
Schlesinger
Bradley E
BE
Britigan
D000154:Aconitate Hydratase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D000963:Antimetabolites / Q000378:metabolism / Q000494:pharmacology*; D000995:Antitubercular Agents / Q000378:metabolism / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015169:Colony Count, Microbial; D004195:Disease Models, Animal; D005708:Gallium / Q000378:metabolism / Q000494:pharmacology*; D007501:Iron / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000254:growth & development / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors / Q000378:metabolism; D013154:Spleen / Q000187:drug effects / Q000382:microbiology / Q000473:pathology; D016019:Survival Analysis; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy* / Q000382:microbiology / Q000401:mortality / Q000473:pathology
D000963:Antimetabolites; D000995:Antitubercular Agents; D001426:Bacterial Proteins; D005708:Gallium; D007501:Iron; D012264:Ribonucleotide Reductases; D000154:Aconitate Hydratase; C027235:gallium nitrate