A ferritin mutant of Mycobacterium tuberculosis is highly susceptible to killing by antibiotics and is unable to establish a chronic infection in mice.
Iron is an essential, elusive, and potentially toxic nutrient for most pathogens, including Mycobacterium tuberculosis. Due to the poor solubility of ferric iron under aerobic conditions, free iron is not found in the host. M. tuberculosis requires specialized iron acquisition systems to replicate and cause disease. It also depends on a strict control of iron metabolism and intracellular iron levels to prevent iron-mediated toxicity. Under conditions of iron sufficiency, M. tuberculosis represses iron acquisition and induces iron storage, suggesting an important role for iron storage proteins in iron homeostasis. M. tuberculosis synthesizes two iron storage proteins, a ferritin (BfrB) and a bacterioferritin (BfrA). The individual contributions of these proteins to the adaptive response of M. tuberculosis to changes in iron availability are not clear. By generating individual knockout strains of bfrA and bfrB, the contribution of each one of these proteins to the maintenance of iron homeostasis was determined. The effect of altered iron homeostasis, resulting from impaired iron storage, on the resistance of M. tuberculosis to in vitro and in vivo stresses was examined. The results show that ferritin is required to maintain iron homeostasis, whereas bacterioferritin seems to be dispensable for this function. M. tuberculosis lacking ferritin suffers from iron-mediated toxicity, is unable to persist in mice, and, most importantly, is highly susceptible to killing by antibiotics, showing that endogenous oxidative stress can enhance the antibiotic killing of this important pathogen. These results are relevant for the design of new therapeutic strategies against M. tuberculosis.
Public Health Research Institute and Department of Medicine, University of Medicine and Dentistry of New Jersey, New Jersey Medical School, Newark, New Jersey, USA.
Ruchi
R
Pandey
G Marcela
GM
Rodriguez
D000222:Adaptation, Physiological / Q000187:drug effects; D000818:Animals; D000995:Antitubercular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D002908:Chronic Disease; D005260:Female; D005293:Ferritins / Q000235:genetics / Q000378:metabolism*; D017353:Gene Deletion; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology*; D006706:Homeostasis; D007501:Iron / Q000378:metabolism / Q000494:pharmacology; D008168:Lung / Q000382:microbiology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000502:physiology*; D018384:Oxidative Stress; D014397:Tuberculosis, Pulmonary / Q000188:drug therapy / Q000382:microbiology* / Q000473:pathology
D000995:Antitubercular Agents; D005293:Ferritins; D007501:Iron