The long term goal of this project is to understand the genetic regulation of metabolism in the human pathogenic bacterium Mycobacterium tuberculosis (Mtb). Regulation of the metabolic and energy generating pathways is key to adapting to changing host environments during infection. Mtb in the host catabolizes fatty acids and lipids for energy-generating compounds. Propionyl-CoA, a by-product of odd-chain fatty acid oxidation, must be further metabolized through either the methylcitrate cycle (MC) or the methylmalonyl (MM) pathway. The methylcitrate cycle provides growth intermediates by oxidizing propionyl-CoA to pyruvate and succinate. The methylmalonyl pathway is an essential pathway in Mtb and the product, methylmalonyl-CoA, is the building block for branched-chained fatty acid and lipid biosynthesis, specifically for the lipids phthiocerl dimycocerosate (PDIM) and the sulfatides (SL). Pathway utilization has the potential consequence of switching between metabolic intermediate synthesis and fatty acid biosynthesis. However, neither the genetic regulation of these two pathways, nor the flux between pathway usages is understood. Therefore, the immediate goal of this project is to understand the regulation of propionyl-CoA metabolism. I have strong evidence that the cAMP-associated transcription factor, Cmr, is a potential regulator of these two pathways. Thus, the role of Cmr on the regulation of these gene classes will be tested, as well as the affect Cmr has regulating the flux between pathway usage. Further, the role of Cmr in Mtb within macrophages in regards to the MC and MM pathway will be determined.
Tuberculosis, caused by M. tuberculosis (Mtb) remains a serious global public health problem. Understanding how Mtb adapts and survives within the human host is imperative for identifying putative new targets for TB vaccines and therapeutics needed for controlling this devastating disease.