# Development of ureadepsipetides for drug-resistant infections

> **NIH NIH R01** · ARIETIS · 2020 · $1,235,145

## Abstract

The goal of this project is to develop UDEP antibiotics, which cause bacterial cells to self-digest
through activation of the ClpP protease. This unique “activating” mechanism causes rapid and
exceptional killing of drug resistant pathogens. UDEPs also have an important advantage – killing of
both metabolically active and dormant forms of pathogens. Many bacteria evade killing by
traditional antibiotics, even surviving high concentrations for prolonged periods by simply growing
slowly or not at all, in the case of persister cells. These surviving cells contribute to phenotypic
antibiotic resistance, cause recurrent infections, and explain why traditional antibiotics are unable
to kill biofilms, which have restricted access to the immune system. However, bacteria cannot
escape death by shutting down or waiting until antibiotic levels drop upon activation of ClpP
proteases by UDEPs. UDEPs not only target antimicrobial resistant pathogens, but may also allow
common infections to be treated more quickly and effectively with less recurrence, while chronic
infections like endocarditis, osteomyelitis, catheter-related bloodstream infections and prosthetic
joint infections could be cured with antibiotics for the first time. A structure guided medicinal
chemistry program led to the discovery of the UDEPs series, many of which have superior drug-like
properties compared to the first generation acyldepsipeptides. Major gains in area under the curve
(AUC), Cmax, half-life, and clearance have been achieved, while maintaining potency. A recent
structural advance has enabled us to prioritize a lead-like UDEP, 3349. This compound displays
efficacy in multiple animal models of infection which are highly predictive for humans, including
septicemia, neutropenic thigh, pneumonia, and in a complicated model of biofilm foreign body
infection. In this study, 3349 will be used to benchmark a sub-library of late leads designed to
further improve druggability to produce a lead candidate suitable to be advanced into pre-clinical
development. These studies will be performed in four aims: (i) Further optimization of late lead
UDEPs using structure and PK guided design; (ii) in vitro pharmacological profiling to maximize
safety, and hollow-fiber models of infection will be used to guide dose selections and the choice of
antibiotic partners; (iii) in vivo efficacy determination in infection models of peritonitis septicemia,
neutropenic thigh, lung pneumonia, implanted catheter biofilms and endocarditis; (iv) Preclinical
development, using detailed in vivo PK/PD dose, dosing interval and target attainment will support
IND-enabling studies. Toxicokinetic studies will support dose selection, toxicology endpoints and
toxicokinetic time points for GLP-compliant studies. These studies will provide the basis for a risk-
benefit assessment prior to meeting with the FDA.

## Key facts

- **NIH application ID:** 9839482
- **Project number:** 5R01AI141193-02
- **Recipient organization:** ARIETIS
- **Principal Investigator:** Michael LaFleur
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,235,145
- **Award type:** 5
- **Project period:** 2018-12-17 → 2023-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9839482

## Citation

> US National Institutes of Health, RePORTER application 9839482, Development of ureadepsipetides for drug-resistant infections (5R01AI141193-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9839482. Licensed CC0.

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