# Structure-based microbially targeted prodrugs

> **NIH NIH R01** · CHILDREN'S HOSP OF PHILADELPHIA · 2024 · $798,784

## Abstract

PROJECT SUMMARY
Antimicrobial drug resistance is an ongoing challenge for many serious diseases, including
staphylococcal infections. Development of new antibiotics to combat methicillin-resistant
Staphylococcus aureus—labeled a “serious threat” by the CDC—is a high priority. During drug
development efforts, poor cellular penetration and drug-like features of compounds are a common
roadblock. The studies in this proposal will advance a novel strategy to overcome this roadblock, by
employing a prodrug approach, in which a bipartite molecule is activated intracellularly to release the
active “warhead.” Central to our strategy is the determination of structure-activity relationships that
define selective prodrug activation within S. aureus bacteria. We will advance this strategy by evaluating
our preliminary prodrug SAR using two classes of inhibitors that are distinct in chemical structure and
intracellular target. We will determine the enzymatic selectivity and evaluate how prodrugging alters
biological properties of inhibitors, using in vitro and in vivo assays. In addition, we will use
crystallographic approaches to delineate the structural features that define selective substrate
recognition. Together, this project will establish and validate our approach for subsequent pre-clinical
optimization of much-needed new antistaphylococcal therapies.

## Key facts

- **NIH application ID:** 10898720
- **Project number:** 5R01AI171514-03
- **Recipient organization:** CHILDREN'S HOSP OF PHILADELPHIA
- **Principal Investigator:** Cynthia Schieck Dowd
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $798,784
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10898720

## Citation

> US National Institutes of Health, RePORTER application 10898720, Structure-based microbially targeted prodrugs (5R01AI171514-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10898720. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*