Tuberculosis (TB) remains a significant public health problem world-wide, resulting in an estimated 10 million new infections and 1.5 million deaths in 2018 alone. Increasing resistance of Mycobacterium tuberculosis (M.tb) to currently available anti-TB drugs threatens much of the progress that has been made toward the global goal of TB elimination over recent years.
Ethionamide (ETH) and prothionamide (PTH) are valuable drugs in the treatment of TB. However, due to their suboptimal bioactivation within the M.tb, high doses are required to achieve clinical efficacy and are typically associated with increasing adverse events, most commonly gastrointestinal intolerance and hepatotoxicity. This results in ETH/PTH not being able to express their full activity. Despite this, ETH/PTH are part of a second-line anti-TB agent for the treatment of multi-drug resistant (MDR)-TB. Small molecules acting on regulators of the ETH/PTH bioactivation pathways in M.tb were shown to both a) boost ETH/PTH activity and b) revert resistance to this antibiotic class. Interestingly, these small molecules (boosters) render ETH/PTH active also against a vast majority of isoniazid-resistant strains.