Synthesis and anti‐mycobacterial characterization of ester protected ethambutol derivatives

The world‐wide health impact of tuberculosis (TB) infection continues to grow, as new drug resistant versions of TB emerge and co‐infections between HIV/AIDS and TB spread. Yet, no new antibiotics for TB infection have been developed in the last thirty years. We have investigated the potential for TB lipases to serve as novel inhibitory targets for TB infection. Specifically, we screened for the ability of novel derivatives of ethambutol, a common antibiotic treatment for TB infection, to inhibit the growth of Mycobacterium smegmatis , a model bacterium for TB infection. We initially synthesized a small library of ester‐protected ethambutol derivatives, using simple esterification reactions between ethambutol and a range of diverse carboxylic acids. The ester‐protected ethambutol derivatives were screened for inhibitory activity toward M. smegmatis growth. The inhibitory potential of ester derivatives of ethambutol was dependent on hydrolase activity, as general serine hydrolase inhibitors blocked the inhibitory action of ethambutol. Ester‐protecting groups on ethambutol derivatives with specific activity toward M. smegmatis are now being refined to precisely define the substrate specificity of mycobacterial hydrolases. Funding provided by Butler University Holcomb research fund.