# Repurposing novel selective drugs for treatment and decolonization of vancomycin resistant enterococci

> **NIH NIH R01** · VIRGINIA POLYTECHNIC INST AND ST UNIV · 2022 · $619,644

## Abstract

Project Abstract:
 Vancomycin-resistant enterococci (VRE) is the second leading cause of drug-resistant hospital-acquired
infections (HAIs) in the US, triggering the Centers for Disease Control and Prevention to classify VRE as a
serious healthcare threat. Despite the prevalence and severity of VRE infections, there are limited number of
effective therapeutic options available for treatment. Moreover, the drugs that are available are also detrimental
to the normal gut microbiota ultimately contributing the problematic cycle of microbial imbalance known as
dysbiosis, which enterococcus takes advantage of in the first place. Thus, there is a significant need for a
treatment that can be used to clear both symptomatic and asymptomatic enterococcus colonization without
damaging the homeostasis of normal gut flora. Unlike the costly and time-consuming process of de novo drug
discovery, drug repurposing is a novel method to reduce the time, cost and risk associated with drug innovation.
Studies proposed in this application build upon discoveries of the potent and narrow spectrum antimicrobial
activity of the FDA-approved drugs, carbonic anhydrase inhibitors (CAIs) (acetazolamide, dorzolamide,
brinzolamide, ethoxzolamide, methazolamide, and dichlorphenamide), in an applicable clinical range, against
highly multidrug-resistant enterococci, including VRE. We have demonstrated both in vitro and in vivo that CAIs
are superior to drug of choice, linezolid, and can be used for treatment of serious VRE infections as well as VRE
decolonization without harming gut microbiota. In addition, we were able to identify a novel antimicrobial target
specific for enterococci that could be exploited in future screening campaigns for new inhibitory scaffolds. Our
team has embarked upon medicinal chemistry optimization and improved the potency of the scaffold versus VRE
by 570-fold (MIC = 0.007 µg/ml for most potent analog) while maintaining no antibacterial activity against normal
gut microbiota. We propose to continue lead optimization and assess the in vivo efficacy in various VRE mouse
models as well evaluate the novel inhibitor’s safety and PK profiles to support future lead selection and
investigational new drug enabling studies.

## Key facts

- **NIH application ID:** 10468002
- **Project number:** 5R01AI148523-05
- **Recipient organization:** VIRGINIA POLYTECHNIC INST AND ST UNIV
- **Principal Investigator:** Mohamed Seleem
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $619,644
- **Award type:** 5
- **Project period:** 2019-09-19 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10468002

## Citation

> US National Institutes of Health, RePORTER application 10468002, Repurposing novel selective drugs for treatment and decolonization of vancomycin resistant enterococci (5R01AI148523-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10468002. Licensed CC0.

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