# Elucidating altered lipid pathways in daptomycin-resistant pathogens

> **NIH NIH K22** · UNIVERSITY OF GEORGIA · 2020 · $161,266

## Abstract

Project Summary
 Alteration of membrane lipids, particularly the reduction of total phosphatidylglycerols (PGs), is a common
daptomycin resistance phenotype across many species of Gram-positive bacteria. These modifications to
membrane lipid content and composition can occur through direct genetic mutations in lipid biosynthetic
pathways or indirect mutations in cell envelope stress response systems that regulate expression of membrane
and cell wall biosynthesis genes. We have previously characterized the altered membrane lipids in daptomycin-
resistant strains of methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococcus
faecalis (VRE), and Corynebacterium striatum and found that: i) daptomycin resistance also significantly affected
non-PG lipids, and ii) the changes manifested only in membrane lipids with specific fatty acid compositions in
MRSA and VRE. Lipid biosynthesis is a promising target for the development of novel therapies for the treatment
of daptomycin resistance due to the lipid-dependent mechanism of daptomycin’s bactericidal action and the
differences between eukaryotic and prokaryotic lipid biosynthetic pathways. However, the membrane lipidomes
of Gram-positive bacteria are diverse in the variety and ratios of lipid classes present and the fatty acid
compositions of those lipids. This diversity presents a challenge to finding common lipid pathways that can be
exploited to disrupt daptomycin resistance, but the central pathways of lipid synthesis and metabolism are
likely to be conserved across diverse daptomycin-resistant species. The long-term goals of this project
are to identify the common and differential pathways in lipid biosynthesis and metabolism that contribute to
daptomycin resistance among different species of Gram-positive bacteria and to identify small molecule
modulators of these pathways that can reverse daptomycin resistance. In Aim 1, we will elucidate common and
differential pathways in lipid metabolism and biosynthesis that are modified in a diverse collection of bacterial
pathogens with daptomycin resistance. We will also examine the fatty acid-dependent nature of lipid changes in
daptomycin-resistant MRSA and VRE. In Aim 2, we will modulate daptomycin resistance with small molecules
targeting lipid biosynthesis and metabolism and evaluate the effects of extracellular free fatty acids on
daptomycin resistance. We expect that the pathways that are conserved among diverse bacteria species with
daptomycin resistance will be universal targets for modulation with small molecules, and these small molecules
will improve daptomycin susceptibility by affecting the lipids and fatty acids that favor daptomycin resistance.
This project will provide new fundamental understanding of the molecular alterations that contribute to
daptomycin resistance and identify novel small molecule interventions that can be adapted into effective
therapeutics for treating infections from multiple species of dapto...

## Key facts

- **NIH application ID:** 9890277
- **Project number:** 1K22AI143919-01A1
- **Recipient organization:** UNIVERSITY OF GEORGIA
- **Principal Investigator:** Kelly M. Hines
- **Activity code:** K22 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $161,266
- **Award type:** 1
- **Project period:** 2020-06-12 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9890277

## Citation

> US National Institutes of Health, RePORTER application 9890277, Elucidating altered lipid pathways in daptomycin-resistant pathogens (1K22AI143919-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9890277. Licensed CC0.

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