Final Report Summary - EVODRTB (Compensatory Evolution and Epistasis in Multidrug-resistant Mycobacterium tuberculosis)
Tuberculosis (TB) is the main cause of human death due to infection in general, and due to antimicrobial resistance (AMR) in particular. A long-standing dogma in the TB field has been that antibiotic-resistant TB bacteria were less virulent and less likely to transmit from person to person. Thus it was generally assumed that the problem of multidrug-resistant TB (MDR-TB) was mainly due to patient non-adherence to treatment. The findings from this project contradict this simplistic view by demonstrating that a substantial part of the MDR-TB problem can be attributed to direct transmission of MDR-TB bacteria from patient to patient. The reason for the enhanced spread of MDR-TB is that not all MDR-TB bacteria are the same; some carry additional mutations, so-called compensatory mutations, that mitigate the initial reduction of transmission fitness caused by the resistance-causing mutations. Importantly, this work showed that these compensatory mutations contribute to the transmission of MDR-TB independently of other known risk factors such as incarceration; prisons are known breeding-grounds for TB. This project also explored the molecular mechanisms of these phenomena and found that different strains of TB bacteria deal with drug resistance in different ways. As a consequence, the level of resistance to a given TB drug differs across drug-resistant strains, which has important implications of the diagnosis of MDR-TB in the clinic.