Mycolic acid like lipids act as substrates for Mycobacterium tuberculosis melH

Abstract

Mycobacterium tuberculosis (Mtb), the pathogenic bacterium that causes tuberculosis, has developed its own ways of evading defense mechanisms to counteract the lethal effects of reactive oxygen species (ROS) generated within the host macrophages during infection. The melH gene present in Mtb and Mycobacterium marinum (Mm) plays an important role to reduce ROS generated during infection. The melH gene encodes for an epoxide hydrolase. Bioinformatics data suggests that encoded enzyme utilizes lipid substrates for its function. Initially, we used a lipid fractionation approach coupled with liquid chromatography mass spectrometry (LC-MS) and treatment with active MelH enzyme to identify potential substrates for MelH. We found classes of mycolic acids, predominantly epoxy mycolic acids accumulate in the melH mutant and upon treatment with MelH are reduced in the lipid fraction. These results provide insight into how MelH encoded in the mel2 operon contributes to Mtb virulence and persistence and present further evidence for potential mechanisms of action if MelH is targeted for antitubercular drug discovery.