Whole genome CRISPRi screening identifies druggable vulnerabilities in drug-resistant Mycobacterium tuberculosis

Tuberculosis (TB) remains a global health threat, aggravated by the emergence of drug-resistant strains. This study aims to identify genes and metabolic pathways with increased vulnerability in drug-resistant Mycobacterium tuberculosis strains compared to their drug-susceptible counterparts. Using CRISPR interference (CRISPRi), we screened for critical pathways unique or shared across resistant strains. The findings reveal potential therapeutic targets, offering new avenues for anti-TB drug development. This approach addresses the urgent need for effective treatments against drug-resistant TB and advances our understanding of its underlying resistance mechanisms. This work highlights how changes in the physiology of drug-resistant strains generate druggable vulnerabilities that can be exploited to improve clinical outcomes.