# Disrupting Dogma: Investigating LPS Biosynthesis Inhibition as an Alternative Mechanism of Action of Aminoglycoside Antibiotics

> **NIH NIH R15** · WESLEYAN UNIVERSITY · 2023 · $474,697

## Abstract

Project Summary
With numerous Gram-negative bacterial species demonstrating antimicrobial drug resistance, the identification
of new inhibitors and the optimization of existing inhibitors is necessary to enable an effective treatment of
illnesses. Recent research efforts in our lab and others have demonstrated that aminoglycosides have minimal
impact on protein synthesis and in fact they potently bind to heptosytransferase I (HepI) in Escherichia coli. This
is an important finding, because it may allow for this class of antibiotics to be dramatically redesigned to be better
drugs with fewer side effects, because the HepI and ribosome binding sites have very different sizes and they
have dramatic differences in charges (HepI is positively charged, while the ribosome is negatively charged). This
proposal will advance efforts to redesign aminoglycoside antibiotics to enhance HepI binding and to reduce
binding to other cellular targets that can lead to side effects like oto- and nephrotoxicity.
Our investigation will address three hypotheses: (1) that aminoglycosides bind to other cellular targets beyond
the ribosome including heptosyltransferase enzymes, (2) understanding the HepI-aminoglycoside interactions
will enable structural modification and optimization of bactericidal activity, and (3) that computational methods
can enhance aminoglycoside redesign. To date, efforts to redesign aminoglycosides for more potent binding to
the ribosome has failed to lead to more potent drugs, and this is likely because the mechanism of action involves
other enzymes like HepI. This work promises to enhance drug discovery efforts while also providing training for
students in my lab and in two upper-level biochemistry courses at Wesleyan in 21st century drug discovery
methods.

## Key facts

- **NIH application ID:** 10653587
- **Project number:** 1R15AI176175-01
- **Recipient organization:** WESLEYAN UNIVERSITY
- **Principal Investigator:** Erika A Taylor
- **Activity code:** R15 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $474,697
- **Award type:** 1
- **Project period:** 2023-07-01 → 2026-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10653587

## Citation

> US National Institutes of Health, RePORTER application 10653587, Disrupting Dogma: Investigating LPS Biosynthesis Inhibition as an Alternative Mechanism of Action of Aminoglycoside Antibiotics (1R15AI176175-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10653587. Licensed CC0.

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