# Subproject 2 C. elegans-Mediated Discovery of Antimicrobial Compounds Against MRSA and VRE

> **NIH NIH P01** · MASSACHUSETTS EYE AND EAR INFIRMARY · 2020 · $440,642

## Abstract

Project Summary 
 MRSA and VRE are pathogenic to Caenorhabditis elegans nematodes. Based on these observations, we 
developed C. elegans-MRSA and C. elegans-VRE screening assays performed in 384-well plates that can 
be used to screen compound libraries, allowing the identification of compounds that prevent host killing that 
would not be detected in traditional in vitro screens for antibiotics. The ability to eliminate highly toxic 
compounds is particularly important for the identification of compounds with activity against bacterial 
membranes, as these compounds can be broadly toxic against membranes of prokaryotic and eukaryotic 
and toxicity is a bottle-neck for the identification of antimicrobial agents that act on the membrane. 
 In the previous funding period, we developed an automated, high throughput C. elegans – MRSA 
screening platform and screened 88,489 small synthetic molecules and obtained 257 verified hits. Among 
these 257 hits, we prioritized FDA approved and other well-studied compounds that we found target the 
bacterial membrane. Additionally, we completed a screen of 39,931 synthetic compounds using a C. elegans 
– VRE infection model assay and obtained 135 verified hits, including 4 VRE inhibitory compounds that block 
the ability of VRE to form a persistent intestinal infection. 
 Our current overall objective is to carry out translational studies to determine whether the compounds we 
have prioritized can be developed as efficacious antimicrobial compounds. We propose to determine the 
modes of action of compounds with activity against the membrane of MRSA (Aim 1) and prioritize anti- 
infective compounds that block VRE colonization of the C. elegans intestine (Aim 2). In Aim 3, we propose to 
take the first steps to further develop these compounds by generating analogs, evaluating basic PK/PD 
characteristics, and performing efficacy studies in mouse models. 
 In summary, we have used C. elegans-based assays to identify novel non-toxic antimicrobial compounds 
some of which can kill bacterial cells that are in a non-planktonic form of growth. We anticipate that the 
proposed studies will allow the discovery of potentially novel targets for antimicrobial drug discovery and 
identify potential lead compounds with activity against multi-drug resistant Gram-positive pathogens.

## Key facts

- **NIH application ID:** 9996467
- **Project number:** 5P01AI083214-13
- **Recipient organization:** MASSACHUSETTS EYE AND EAR INFIRMARY
- **Principal Investigator:** Frederick M Ausubel
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $440,642
- **Award type:** 5
- **Project period:** 2009-09-01 → 2022-02-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9996467

## Citation

> US National Institutes of Health, RePORTER application 9996467, Subproject 2 C. elegans-Mediated Discovery of Antimicrobial Compounds Against MRSA and VRE (5P01AI083214-13). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9996467. Licensed CC0.

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