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.