Iron homeostasis in Mycobacterium tuberculosis is essential for persistence

Tuberculosis, caused by the obligate intracellular pathogen Mycobacterium tuberculosis (Mtb), is responsible for 2-3 million deaths annually worldwide. Intracellular adaptability, which is critical for long-term persistence, requires the pathogen to neutralize host-mediated insults. The iron-sulphur (Fe-S) cofactor is essential for many enzymes critical for such 'adaptation'. The Mtb genome harbors only one putative iron-sulphur cluster (ISC) operon (rv1460-66) predicted to be involved in the generation of the Fe-S cofactor. Except for rv1460, all other genes in this operon are anticipated to be essential. The current study investigated the role of rv1460, an sufR homologue of Mtb (sufR_TB), in maintaining intracellular Fe homeostasis and its implications on mycobacterial pathogenesis. We found that Mtb ISC locus (rv1461-66) was transcribed as a single multigene transcript. We successfully generated the sufR_TB null mutant strain (ΔsufR_TB) of Mtb, suggesting nonessentiality of the gene under normal growth conditions. The mutant strain demonstrated enhanced biofilm generation and failed to grow under a low-Fe condition. Growth characterization studies indicated that SufR_TB-mediated intracellular Fe homeostasis is essential for Mtb to persist in the host. Targeting mycobacterial persistence by inhibiting SufR_TB protein activity may be a novel intervention strategy in tuberculosis treatment.