Erin Wang
Program: Molecular Microbiology and Microbial Pathogenesis
Current advisor: Christina L. Stallings, PhD
Undergraduate university: California Institute of Technology
Research summary
As one of the deadliest pathogens in the world, Mycobacterium tuberculosis (Mtb) was responsible for 10 million infections in 2021. The emergence of drug resistant Mtb presents a major obstacle to combatting this global epidemic. In addition to developing novel antibiotics against Mtb, it is equally important that we direct efforts to optimize existing therapies to stymie the emergence of drug resistance. We previously identified C10 as a compound that promotes killing of Mtb by the frontline antibiotic isoniazid (INH) and 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. Thus, we sought to dissect the mechanism of action of C10 in order to identify novel potential targets for enhancing INH activity against Mtb. We expanded upon our previous work demonstrating that C10 alters Mtb metabolism. We report that C10 diverts carbon flux from the TCA cycle towards branched chain amino acid and propionyl-CoA synthesis, depleting intracellular pyruvate levels and inhibiting gluconeogenesis. We hypothesized that this impairs production of critical cell wall precursors required for biosynthesis of the essential mycolyl-arabinogalactan-peptidoglycan (mAGP) component of the Mtb cell envelope. We discovered that propionate or pyruvate supplementation blocks the ability of C10 to enhance INH activity against Mtb. Through stable isotope tracing using labeled glycerol and pyruvate, we found that supplementation with pyruvate improves glycerol assimilation into mAGP precursors and confirmed using a combination of molecular and biochemical methods that supplementation restores cell wall integrity. Our findings provide us with a deeper understanding of how Mtb responds to INH and C10 perturbation of metabolism, which could contribute to the discovery of novel targets that can be exploited to combat antibiotic resistance and design more effective therapies.
Graduate publications
Harrison GA, Wang ER, Cho K, Mreyoud Y, Sarkar S, Almqvist F, Patti GJ, Stallings CL. 2024 Inducing vulnerability to InhA inhibition restores isoniazid susceptibility in drug-resistant Mycobacterium tuberculosis. mBio, 15(3):e0296823.
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.