Erin Wang

Program: Molecular Microbiology and Microbial Pathogenesis

Current advisor: Christina L. Stallings, PhD

Undergraduate university: California Institute of Technology, 2018

Enrollment year: 2018

Research summary
Metabolic determinants of isoniazid susceptibility in Mycobacterium tuberculosis.

Mycobacterium tuberculosis (Mtb) is the leading cause of death by an infectious agent and the emergence of drug resistant Mtb presents a major obstacle to combatting this global epidemic. We previously identified C10 as a compound that promotes killing of Mtb by the frontline antibiotic isoniazid (INH). We serendipitously discovered that C10 re-sensitizes a katGW328L INH-resistant mutant to killing by INH. This is the first instance of re-sensitization of a genetically resistant mutant that has been reported in Mtb, making C10 an incredibly valuable tool we can leverage to design new strategies for reversing drug resistance. We found that C10 blocks accumulation of MAs during hypoxia and inhibits biofilm formation and cording, which are virulence-associated processes that require mycolic acids (MAs). C10 also 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. 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. We hypothesize that C10 dysregulates lipid biosynthetic pathways, rendering the bacteria exquisitely sensitive to INH inhibition of MA synthesis. Our experiments will provide us with a deeper understanding of how Mtb responds to INH and uncover novel targets that can be exploited to combat antibiotic resistance and design more effective therapies.

Graduate publications
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. PMCID: PMC7372600

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. PMCID: PMC7608022