Exploring and exploiting trehalose metabolism in rifampicin-resistant mycobacterium tuberculosis
Active Project Grant Awarded Last action
- Award ID
- F30AI197421
- Recipient
-
Weill Medical College Of Cornell University UEI YNT8TCJH8FQ8
- Awarding agency
-
National Institute of Allergy and Infectious Diseases
National Institutes of Health, Department of Health and Human Services
- Obligated
- $55,114
Award facts
- Assistance listing
- 93.855 Allergy and Infectious Diseases Research
- Completion date 0% complete
- Place of performance
- New York, NY 10065, USA
Award details come from USAspending.gov.
Description
- Abstract
- Tuberculosis (TB) remains a leading global health challenge, with rifampicin-resistant (RIFR) mycobacterium tuberculosis (MTB) posing a significant barrier to effective treatment. RIFR mutations, such as ΒS450L in RNA polymerase, alter genetic vulnerabilities, changing the fitness cost imposed by the knockdown of various genes. Our group identified numerous enzymes involved in trehalose synthesis, and in particular trehalose-6- phosphate synthase (OTSA), as having enhanced vulnerability in ΒS450L compared to rifampicin-susceptible (RIFS) MTB. Although trehalose is a crucial disaccharide involved in MTB physiology, my preliminary data suggest that the heightened vulnerability of ΒS450L to OTSA knockdown is not merely a product of trehalose deficiency. In this proposal, I will investigate the mechanistic basis of this phenomenon, testing the central hypothesis that OTSA knockdown produces metabolic disturbances that disproportionately impact ΒS450L MTB. In aim 1, I will determine the physiological consequences of OTSA knockdown in rifampicin-susceptible and ΒS450L MTB through targeted metabolomic and transcriptomic approaches. In aim 2, I will identify genetic interactions that modulate the fitness cost of OTSA knockdown in ΒS450L MTB using a genome-wide crispr-interference (CRISPRI) screen. I anticipate that these studies will elucidate both the molecular basis and physiological consequences of OTSA knockdown in ΒS450L MTB. In aim 3, I will evaluate whether targeting OTSA might be an effective strategy to slow the evolution of rifampicin resistance and reduce ΒS450L MTB survival during infection. These proposed experiments will enhance our understanding of metabolic adaptations in drug-resistant MTB and inform novel therapeutic strategies to combat RIFR TB. This fellowship will support my training in the weill cornell/rockefeller/sloan kettering TRI-institutional MD-PHD program, including my doctoral work in the laboratory of DR. Jeremy rock at rockefeller and the remainder of my medical training at weill cornell. The training plan outlined in this fellowship project is designed to optimally prepare me for a research career as an independent principal investigator and physician-scientist.
Quick answers
Who received award F30AI197421?
F30AI197421 was awarded to Weill Medical College Of Cornell University by National Institute of Allergy and Infectious Diseases (National Institutes of Health) on February 25, 2027.
How much is award F30AI197421 worth?
$55,114 has been obligated on F30AI197421.
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