Characterization Of The Molecular Mechanisms Involved In Ethionamide Activation in Mycobacteria

Abstract

Approximately one-third of the world population is presently infected with the highly infectious Mycobacterium tuberculosis. With dwindling treatment options for multi-drug resistant tuberculosis (MDR-TB) that are decades old, it has become imperative to develop shorter, more efficient anti-TB therapies with existing drugs. One of the most efficient second-line drugs to date for the treatment of MDR-TB is the pro-drug ethionamide (ETH). As a pro-drug that requires activation within the mycobacterial cell in order to exert its bactericidal effects, the current model for ETH bio-activation involves a Bayer-Villiger monooxygenase EthA and a repressor, EthR, which binds to the promoter region of ethA. However, the molecular mechanisms of ETH activation have not been completely deciphered, and the physiological role in mycobacteria also remains uncharacterized. This thesis aims to further characterize the role of the EthA/R system in both the physiology and virulence of mycobacteria, and in ETH bio-activation.