# Bioorganic Approaches Toward Novel Antimicrobial Agents Against Gram-Negative Bacteria

> **NIH NIH R35** · VANDERBILT UNIVERSITY · 2022 · $69,223

## Abstract

Principle Investigator/Program Director (Last, first, middle): Townsend, Steven D.
Parent Grant Summary/Abstract:
Multi-drug resistant (MDR) Gram-negative bacterial infections are an ongoing challenge to public health. Indeed,
4 of the ESKAPE pathogens recently highlighted as responsible for the majority of hospital acquired infections
are Gram-negative pathogens. Although it is clear that novel antibiotics for Gram-negative infections are
desperately needed, there has been minimal progress in this regard, and it has been over five decades since a
new class of drugs have been introduced for Gram-negative bacteria. The development of new antibiotics to
treat these pathogens is complicated by the fact that Gram-negative bacteria have an impenetrable membrane
that confers intrinsic resistance to antimicrobial agents. The broad objective of this program is to study
glycoconjugates to combat Gram-negative pathogens. We have made two major discoveries that suggests
human milk oligosaccharides (HMOs) may be transformative in this regard. First, HMOs cause major changes
to the behavior of bacteria, with strong effects on growth and the formation of biofilms, architectures that aid in
bacterial survival. We have also observed that HMOs function as potent adjuvants, potentiating the activity of
intracellular-targeting antibiotics by increasing cell permeability. These two discoveries form the foundation of
the projects proposed in this application. In Project 1 we seek to characterize the impact of HMOs on Gram-
negative causes of microbiome imbalance. In Project 2 we will explore HMOs in combination therapies against
A. baumannii, an important Gram- negative pathogen. In Project 3 we investigate the chemistry and biochemistry
of the mollemycin glycopeptides, a rare glycopeptide with antimicrobial activity against Gram-negative
pathogens. While not sourced from milk, we plan to leverage our experience in human milk science to study the
biochemistry of the mollemycins. A significant output of this work is a mechanistic understanding of the types of
compounds that can enter Gram-negative bacteria.
Supplement Abstract:
The aminoglycoside antibiotics (AGAs) are potent broad-spectrum antibiotics that show excellence activity
against aerobic, gram-negative pathogens. AGAs are limited by significant side effects, one of which is ototoxicity
or AGA‐induced permanent hearing loss. Ototoxicity affects ca. 20% of the patient population. Nephrotoxicity, or
the rapid erosion of kidney function is also a key side effect. Lastly, and perhaps unexpectedly, resistance
evolution is problematic in AGA usage. This proposal focuses on the synthesis and biological evaluation of novel
aminoglycoside derivatives against gram-negative ESKAPE pathogens, a family of multidrug resistant bacteria.
Synthetic AGAs will undergo screening for inhibition of bacterial and eukaryotic ribosomes, representative of
antibacterial activity and toxicity, respectively. The results of these assays w...

## Key facts

- **NIH application ID:** 10620040
- **Project number:** 3R35GM133602-04S1
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Steven D. Townsend
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $69,223
- **Award type:** 3
- **Project period:** 2019-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10620040

## Citation

> US National Institutes of Health, RePORTER application 10620040, Bioorganic Approaches Toward Novel Antimicrobial Agents Against Gram-Negative Bacteria (3R35GM133602-04S1). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10620040. Licensed CC0.

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