# Metabolic Impact of Tryptophan Synthase Inhibition in Mycobacterium tuberculosis and Implications for Rational Combination Therapy

> **NIH NIH F31** · WEILL MEDICAL COLL OF CORNELL UNIV · 2020 · $45,520

## Abstract

PROJECT SUMMARY
Kyle Planck is a PhD Student in the pharmacology program at Weill Cornell Medicine in New York City, where
he is a member of the Rhee research laboratory. His research interests include developing a deeper
understanding of the biochemical processes at work in pathogenic microorganisms and employing this
knowledge to formulate clinically relevant treatments for the infections they cause. At Weill Cornell, Kyle carries
out this work specifically within the context of tuberculosis (TB), which is the world’s leading cause of death from
an infectious disease. This fellowship application details a research plan that incorporates the acquisition of
technical skills with mentorship and career guidance in order to prepare him for his career goal of establishing
an independent research laboratory at an academic medical center.
Kyle has extensive research experience in biology, biochemistry, and pharmacology, and he brings that research
foundation to his graduate work and this proposal, which integrates systems level “omics” analytical approaches
with classical microbiological and biochemical techniques. The goal of this project is to characterize the metabolic
effects of inhibiting the tryptophan biosynthesis pathway, which is essential to the survival of Mycobacterium
tuberculosis (Mtb)—the causative agent of TB—and is being pursued as a source of potential drug targets. The
project has two aims: to determine the mechanism of killing elicited by allosteric chemical inhibitors of tryptophan
synthase (TrpAB), which our preliminary data suggests to be more complex than simple enzyme product
depletion, and to survey whether TrpAB inhibition results in collateral vulnerabilities in other metabolic pathways
that may be targetable as well. By carrying out these investigations, Kyle hopes to provide evidence for the
mechanism of action of these drug candidates, shed light on the process of tryptophan biosynthesis and its
regulation in Mtb, and reveal novel possibilities for combination therapy, which is required for the effective
treatment of tuberculosis.
This research strategy proposes to answer these questions by incorporating standard microbiological techniques
such as growth curves and colony-forming unit enumeration in tandem with cutting-edge technologies such as
inducible genetic knockdown strains, RNA sequencing, targeted and untargeted LC/MS-based metabolomics,
and CRISPR interference to probe the biology of Mtb in the context of TrpAB inhibition compared to no drug
controls. Systems level omics modalities such as metabolomics and transcriptomics will be used to survey the
genetic and metabolic networks controlling tryptophan biosynthesis in Mtb, which will then be validated with
genetic and biochemical approaches.

## Key facts

- **NIH application ID:** 10066828
- **Project number:** 1F31AI154832-01
- **Recipient organization:** WEILL MEDICAL COLL OF CORNELL UNIV
- **Principal Investigator:** Kyle Planck
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,520
- **Award type:** 1
- **Project period:** 2020-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10066828

## Citation

> US National Institutes of Health, RePORTER application 10066828, Metabolic Impact of Tryptophan Synthase Inhibition in Mycobacterium tuberculosis and Implications for Rational Combination Therapy (1F31AI154832-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10066828. Licensed CC0.

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