Researchers from the Indian Institute of Science (IISc), collaborating with NCBS and InStem, have identified a crucial gene involved in iron-sulphur cluster production that plays a key role in TB bacterium persistence.

The significant mechanism enables the tuberculosis (TB) bacterium to persist in the human host for decades. This study, featured in Science Advances, highlights the prolonged presence of Mycobacterium tuberculosis (Mtb) in the human body without symptoms. In asymptomatic cases, Mtb hides within oxygen-limiting lung pockets, entering dormancy to evade the immune system and TB drugs.

Amit Singh, Associate Professor at MCB and the study’s corresponding author, emphasises the importance of understanding persistence to eradicate TB, as it creates a bacterial reservoir prone to reactivation. The team cultivated Mtb in a high-tech Bio safely Level-3 facility, investigating proteins dependent on iron-sulphur clusters. These clusters, comprising iron and sulphur atoms, are critical for processes like energy production and respiration, allowing bacteria to survive lung conditions and cause infection.

The researchers delved into the production of iron-sulphur clusters by the SUF operon and a single gene, IscS. They generated a mutant Mtb lacking the IscS gene, revealing its predominant role in cluster production under normal and oxygen-limiting conditions. Facing oxidative stress, damaged clusters prompted an increased demand, activating the SUF operon. Examining disease progression, the team infected mice with the IscS-deficient Mtb, resulting in severe disease rather than the typical chronic infection. Without IscS, the hyperactivated SUF operon reduced Mtb persistence in mice.

Notably, bacteria lacking IscS were susceptible to certain antibiotics, prompting exploration of combination therapies targeting IscS and SUF for enhanced efficacy. Singh envisions that comprehending IscS and SUF systems in Mtb could pave the way for eradicating TB persistence.

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