# Hybrid Antibiotics for Persistent Infections

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2024 · $842,568

## Abstract

Abstract
The goal of this project is to optimize and study the pharmacology of dual-targeting urea depsipeptide
(UDEP)-rifamycin hybrid antibiotics. These new agents have encouraging potential to treat biofilm-
associated and complicated Gram-positive infections including bacteremia, prosthetic joint
infections, and infective endocarditis, which are difficult to cure with standard of care antibiotics such
as vancomycin and cause significant mortality. Most antibiotics require active bacterial growth to
work effectively. Some bacteria evade killing by traditional antibiotics by growing slowly or not at all,
allowing for survival even at high drug concentrations for prolonged periods. These surviving cells
contribute to antibiotic tolerance and resistance, cause recurrent infections, prolong antibiotic
therapy, and increase associated patient care costs. Recently, we have been using structure-based
design to optimize the pharmacology of UDEP antibiotics, which overcome antibiotic tolerance by
target non-dividing bacteria. UDEPs activate the ClpP protease causing uncontrolled proteolysis,
killing stationary phase, dormant, antibiotic-tolerant cells, and biofilms. Rifampin, currently
prescribed in combination with other antibiotics to treat M. tuberculosis (MTB) and prosthetic joint
infections (PJI), also has activity against non-dividing cells by inhibiting DNA-dependent RNA
polymerase and blocking RNA elongation during transcription. In addition to sharing activity against
slowly-growing bacteria, UDEPs and rifampin also share the requirement to be used in combination
with other antibiotics to prevent resistance development. We hypothesized that synthesizing a dual-
targeting UDEP-rifampin hybrid antibiotic would result in significantly less resistance development
and have the potential to achieve unprecedented activity against biofilms and difficult-to-treat
infections. A single molecule has many advantages over a combination, for example, there is no need
to match the pharmacokinetics, and dosing is simpler. In this proposal, we plan to carefully optimize
UDEP-Rifamycin hybrid antibiotics using a detailed synthesis and testing cascade to ensure agents are
developed that have potent activity against persisters in vitro and in vivo, and a safe pharmacological
profile. The mode of action of the emerging leads will be carefully profiled to study their target
engagement, resistance development, effects on growing and non-growing cells.

## Key facts

- **NIH application ID:** 10935961
- **Project number:** 5R01AI180231-02
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Michael LaFleur
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $842,568
- **Award type:** 5
- **Project period:** 2023-09-26 → 2028-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10935961

## Citation

> US National Institutes of Health, RePORTER application 10935961, Hybrid Antibiotics for Persistent Infections (5R01AI180231-02). Retrieved via AI Analytics 2026-06-09 from https://api.ai-analytics.org/grant/nih/10935961. Licensed CC0.

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