Abstract 1349 A CTPase Nudix Hydrolase from Mycobacterium tuberculosis as a Potential Novel Antibiotic Target

Mycobacterium tuberculosis (Mtb) currently infects ∼1/4 of the world's population, kills ∼1.5 million people annually, and there are many strains that are multidrug resistant. Thus, investigating potential novel antibiotic targets for Mtb is essential. We have been systematically discovering the activity for and characterizing the Nudix hydrolases from Mtb as potential drug targets due to their ability to hydrolyze substrates involved in important metabolic and pathogenic processes. One Nudix hydrolase from Mtb that we have been studying is a (d)CTPase, which has an ortholog in E. coli. One substrate for this enzyme is CTP, which is the feedback inhibitor of pyrimidine biosynthesis, and a precursor to lipid biosynthesis including cell membrane formation; the CTPase may help regulate these pathways through degradation of CTP. Another substrate for this enzyme is 5-Methyl-dCTP. There are some bacteriophage that can synthesize 5-Methyl-dCTP. Thus, this bacterial (5-Methyl-)(d)CTPase could be a defense mechanism against phage infection, which we are in the process of testing by comparing phage infection of the wildtype E. coli, knockout E. coli, and the knockout complemented with the Mtb enzyme. If our (d)CTPase is part of a defense mechanism against phage, targeting this enzyme and infecting with phage could be a treatment against Mtb. This work has been funded by an NIH AREA grant and a CUR-Goldwater award.