Program: Molecular Microbiology and Microbial Pathogenesis
Current advisor: Christina L. Stallings, PhD
Undergraduate university: California Inst. of Tech.
Mycobacterium tuberculosis (Mtb) adopts a non-replicating state in response to host-derived stresses. Non-replicating bacilli are tolerant to several frontline antibiotics but remain vulnerable to drugs targeting energy homeostasis. We previously identified C10 as a compound that decreases oxygen consumption and ATP levels, making C10 a promising tool for dissecting the link between ATP homeostasis and drug tolerance. C10 induces methylcitrate cycle (MCC) enzymes PrpD, PrpC, and their transcriptional activator PrpR, and also increases levels of MCC metabolites propionyl-CoA, 2-methylcitrate, and methylmalonyl-CoA, which can be derived from odd-chain fatty acid catabolism. C10 treatment also altered Mtb lipid composition and inhibited the lipid-dependent processes of biofilm formation and cording. Supplementation with exogenous propionate rescued Mtb susceptibility to C10, suggesting increased propionate levels support growth during C10 treatment. The MCC metabolizes propionate into succinate and pyruvate, but can also run in reverse to make propionyl-CoA, an important precursor cell envelope lipids. My project aims to elucidate unexplored connections between Mtb energy homeostasis and lipid and central carbon metabolism, revealing novel mechanisms by which Mtb compensates for ATP depletion.
Samuels AN, Wang ER, Harrison GA, Valenta JC, Stallings CL. 2022 Understanding the contribution of metabolism to Mycobacterium tuberculosis drug tolerance. Front Cell Infect Microbiol, 12():958555.
Bennion BG, Croft CA, Ai TL, Qian W, Menos AM, Miner CA, Frémond ML, Doisne JM, Andhey PS, Platt DJ, Bando JK, Wang ER, Luksch H, Molina TJ, Roberson EDO, Artyomov MN, Rösen-Wolff A, Colonna M, Rieux-Laucat F, Di Santo JP, Neven B, Miner JJ. 2020 STING Gain-of-Function Disrupts Lymph Node Organogenesis and Innate Lymphoid Cell Development in Mice. Cell Rep, 31(11):107771.
Miner JJ, Platt DJ, Ghaznavi CM, Chandra P, Santeford A, Menos AM, Dong Z, Wang ER, Qian W, Karozichian ES, Philips JA, Apte RS. 2020 HSV-1 and Zika Virus but Not SARS-CoV-2 Replicate in the Human Cornea and Are Restricted by Corneal Type III Interferon. Cell Rep, 33(5):108339.