# Harnessing Amide Linkers for Antitubercular Drug Development

> **NIH NIH F30** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $44,408

## Abstract

PROJECT SUMMARY
Tuberculosis (TB) is a global health crisis. As the second leading cause of death due to infectious disease, it
claims roughly 1.5 million lives a year. Although TB can be treated, the curative regimen is complicated and
takes several months. Drug-resistant Mycobacterium tuberculosis (Mtb), including totally drug-resistant strains,
is steadily increasing in prevalence. Therefore, novel therapeutics with the potential to decrease treatment
duration and increase barriers to resistance are essential for disease eradication. Most TB drug discovery
programs have taken target-based approaches and largely ignored intrabacterial metabolism. However, several
first- and second- line antituberculars penetrate Mtb as prodrugs and are intrabacterially metabolized into their
active form. When faced with the markedly lipid-rich, hydrophobic environment of the Mtb cell envelope, prodrugs
have the ability to enter the cell and subsequently release more polar, Mtb-active moieties within the bacterium.
Most Mtb prodrugs are activated by non-essential enzymes, and, as a consequence, resistance develops
quickly. For example, pyrazinamide (PZA), a key first-line antitubercular that enables a shortened TB drug
regimen, is activated to pyrazinoic acid (POA) by the non-essential amidase PncA, and the vast majority of PZA
resistance is caused by mutations in this activating gene. Notably, several other Mtb amidases have also been
shown to metabolize amide antituberculars, thereby activating prodrugs and inactivating active drug compounds.
We hypothesize that we can harness Mtb amidases to design and activate amide prodrugs within Mtb that are
active in drug-resistant disease and that have increased barriers to resistance. Our proposal aims to 1) study
the amide-amidase interactions to identify amide prodrugs that are activated by more than one amidase and 2)
link POA to amine metabolites from parent compounds that demonstrate amide hydrolysis within Mtb to generate
potential POA-releasing conjugates that are activated by non-PncA amidases. The majority of amidases are
non-essential and likely have overlapping functions, enabling the discovery of amide-containing antituberculars
that are activated by multiple amidases. Furthermore, the release of POA by amidases other than PncA would
retain PZA-like activity in PZA-resistant strains, restoring the activity of a first-line antitubercular critical for shorter
TB regimens. This approach will introduce a novel framework for TB prodrug discovery that can be applied to
other classes of small molecules and their activating enzymes. In all, the proposed project and training plan will
greatly further my development as a researcher and independent scientific thinker by introducing me to new
scientific concepts and techniques and providing ample opportunity for me the integrate my research and clinical
experiences. Together, Rutgers New Jersey Medical School, the Public Health Research Institute, and the
Global TB Ins...

## Key facts

- **NIH application ID:** 10825897
- **Project number:** 1F30AI176796-01A1
- **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES
- **Principal Investigator:** Swetha Kodali
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $44,408
- **Award type:** 1
- **Project period:** 2024-02-01 → 2026-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10825897

## Citation

> US National Institutes of Health, RePORTER application 10825897, Harnessing Amide Linkers for Antitubercular Drug Development (1F30AI176796-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10825897. Licensed CC0.

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