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

> **NIH NIH R35** · VANDERBILT UNIVERSITY · 2020 · $298,678

## Abstract

Project Summary
 Multi-drug resistant (MDR) Gram-negative bacterial infections are an ongoing challenge to public
health. Indeed, 4 of the 6 “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.

## Key facts

- **NIH application ID:** 10003364
- **Project number:** 5R35GM133602-02
- **Recipient organization:** VANDERBILT UNIVERSITY
- **Principal Investigator:** Steven D. Townsend
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $298,678
- **Award type:** 5
- **Project period:** 2019-09-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10003364

## Citation

> US National Institutes of Health, RePORTER application 10003364, Bioorganic Approaches Toward Novel Antimicrobial Agents Against Gram-Negative Bacteria (5R35GM133602-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10003364. Licensed CC0.

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