HYDERABAD — Scientists at the CSIR-Centre for Cellular and Molecular Biology (CCMB) have cracked the internal cargo network of the bacterium behind tuberculosis, pinpointing mechanical weaknesses that could yield fresh medicines against hard-to-treat infections. The discovery zeroes in on Mycobacterium tuberculosis, an airborne pathogen that infects millions and frequently defeats standard front-line antibiotics.
Facing down this pathogen is an urgent priority. India shoulders nearly a quarter of all global tuberculosis cases and roughly a third of all drug-resistant strains, according to official data from the World Health Organisation’s Global TB Report 2025. Standard therapies force patients onto rigorous multi-antibiotic regimens that drag on for months—and often fail when resistant mutant strains take hold.
To locate chinks in the pathogen's armour, CCMB Director Vinay Kumar Nandicoori led an investigation to map the bacterium's complete protein transport network. Working alongside teams from the Institute of Mathematical Sciences in Chennai and the Translational Health Science and Technology Institute in Faridabad, the researchers deployed computational models alongside laboratory cultures. They charted 92 essential components and nearly 200 molecular reactions that the microbe uses to shuttle proteins across its cellular boundaries, including the general Sec pathway, the Twin-Arginine Translocation (Tat) system, and specialised ESX export systems.
Bacteria rely on this transit system to feed, multiply, and dodge human immune attacks. "Protein secretion acts like a delivery system inside the bacterium and is vital for its survival," said Dr Jagadeeshwari Uppada, joint first author of the study alongside Dr Priyadarshini Sanyal. To test the system's fragility, the researchers turned to CRISPR-based gene-silencing tools to choke off two primary routes: the SecA1 pathway and the Tat system. The response was immediate. Bacterial multiplication stalled sharply in both laboratory cultures and inside living immune cells.
And the damage went deeper. Disrupting SecA1 halted the movement of more than 100 vital proteins, while disabling the Tat system trapped around 140 proteins inside the cell. Deprived of these structural building blocks, the bacterial cell envelope warped and turned permeable. Internal proteins spilled into the surrounding medium—causing the microbe's protective coat to break down from within. As Dr Nandicoori pointed out, the breakdown exposes an inseparable link between protein export and the physical integrity of the bacterial envelope, the key barrier that lets tuberculosis persist inside lung tissue for years.
Published in the peer-reviewed journal Molecular & Cellular Proteomics, the research outlines a precise roadmap of bacterial vulnerabilities. Yet turning these target pathways into finished medicines will require several more years of drug design and clinical screening. For medical researchers fighting India's drug-resistant caseload, mapping these 92 targets provides the clearest blueprint yet to bypass existing antibiotic resistance.