# A New Approach to Treat Prosthetic Joint Infections with a ClpP Activating Antibiotic

> **NIH NIH R44** · ARIETIS · 2021 · $995,100

## Abstract

The goal of this project is to develop a new class of urea-depsipeptide (UDEP) antibiotics to treat prosthetic joint
infections (PJI). UDEPs kill bacteria through activation of the ClpP protease, causing cells to self-digest. This unique
activating mechanism allows UDEPs to kill biofilms and non-growing persister cells, which are prevalent in PJI and
explain why current antibiotics are largely ineffective. Current therapies involve weeks to months of antibiotic
treatment, debridement surgeries, and medical device replacement. UDEPs have the potential to minimize surgical
interventions due to PJI and improve patient care. PJI are primarily caused by the Gram-positive pathogens
Staphylococcus aureus and epidermidis and the UDEPs are potently active against these pathogens, including multi-drug
resistant strains. A recent advance in our UDEP medical chemistry program yielded a new compound which has
improved safety, solubility, and bone penetration compared to first generation UDEPs. A preliminary study found that
the compound was effective in a K-wire femur medullary canal implant model of PJI, which is known to be difficult to
treat. In this project, we will evaluate if the compound is an acceptable pre-clinical candidate for PJI by testing it in a
series of in vitro and in vivo studies focused on this indication. Specifically, the aims are to 1) scale up the compound; 2)
determine the microbiological and biofilm killing effect against the main pathogens isolated from PJI; and 3) determine
the efficacy of the compound in mouse and rabbit models of PJI.

## Key facts

- **NIH application ID:** 10139185
- **Project number:** 1R44AI157081-01
- **Recipient organization:** ARIETIS
- **Principal Investigator:** Michael LaFleur
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $995,100
- **Award type:** 1
- **Project period:** 2021-03-08 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10139185

## Citation

> US National Institutes of Health, RePORTER application 10139185, A New Approach to Treat Prosthetic Joint Infections with a ClpP Activating Antibiotic (1R44AI157081-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10139185. Licensed CC0.

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