Mycobacterium tuberculosis (Mtb) is the leading cause of bacterial infectious disease mortality worldwide. Thus, there is a critical need for the development of new therapeutic agents for the treatment of Mtb. These new therapies will ideally target new pathways and will posses mechanisms of action that are divergent from current Mtb drugs. Adenylating enzymes of Mtb have recently emerged as attractive targets for therapeutic drug development. Mtb contains more than 100 adenylating enzymes (AEs), which play vital roles in many aspects of the metabolism of the pathogen. Two families of Mtb AEs have attracted attention for their direct role in the survival of Mtb: aryl acid adenylating enzymes (AAAEs) and fatty acid adenylating enzymes (FadDs). Inhibitors, developed in the Aldrich lab, that individually target each of these AEs possess impressive anti-tubercular activity. Since AEs are structurally and functionally homologous, an understanding of the selectivity of the designed AE inhibitors is essential to elucidating their mechanism of action. Therefore, the objectives of this application are to develop chemical probes to study Mtb AEs and their inhibition. We plan to accomplish this objective by synthesizing activity-based chemical probes that are specific towards AAAEs and FadDs. Using proteomic techniques, these chemical probes will ultimately identify protein targets of AE inhibitors developed in the Aldrich lab.
The proposed research is directly relevant to public health since it is aimed at illuminating the mechanism of action of two potent anti-tuberculosis therapeutic agents. Application of these findings should validate new therapies to alleviate the burden of tuberculosis on global human health.