Project Summary This project utilizes translational approaches to use novel assays to understand the emergence of resistance to drugs to treat Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB). Drug-resistant TB incidence has increased 80% worldwide over the past 15 years with high mortality, prolonged treatment course, and poor outcomes. Global multi-drug resistant TB (MDR-TB) cure rates average 65% and as many as 11% of MDR-TB patients develop amplification of drug-resistance on treatment. While emergent drug-resistance is a major challenge it is often detected too late. This application will study pairs of Mtb strains from patients that had drug-susceptible TB at baseline then developed drug-resistant TB. There is extensive clinical and adherence data for these patients. Functional assays for drug-resistance mechanisms will be done to better understand development of drug-resistance under treatment.