Rv1625/cya agonists such as TBD11 impact multiple pathways in Mtb (ATP depletion, block cholesterol utilization, block fatty acid utilization) and this compound shortens treatment in mice when combined with BPaL. It is unclear what pathway(s), when corrupted/blocked, contributes to this BPaL+TBD11 potentiation. Thus, we are focused on determining which physiological aspects impacted by TBD11 contribute to the BPaL potentiation while identifying Mtb biomarkers (transcriptional and metabolite) generated in response to this combination treatment. We anticipate that this project will provide information needed to guide rational drug discovery efforts aimed at potentiating BPaL-based regimens.

TBD11 stimulates cAMP production in Mtb and this is central to the mechanism of action for this compound. Our preliminary studies indicate that co-treating Mtb with two independent cAMP stimulators (TBD11 and CU35) results in a novel form of potentiation associated with driving Mtb to produce yet even more cAMP. Based on this finding we will develop HTS assays centered on detecting identifying new cAMP stimulators that act independent of Rv1625/cya. We plan to identify the putative target for any hit compounds and evaluate how treating Mtb with multiple cAMP stimulators may potentiate with the BPaL regimen.