# Regulation of lipid metabolism in bacteria

> **NIH NIH R01** · ST. JUDE CHILDREN'S RESEARCH HOSPITAL · 2020 · $723,024

## Abstract

Abstract: Membrane phospholipid biosynthesis and fatty acid metabolism are vital facets of bacterial physiology
that are poorly understood. The long-term goal is to define the diversity of biochemical mechanisms used by
bacterial pathogens to obtain lipid nutrients from the host, and to modify host unsaturated fatty acids to create
new signaling molecules that alter the immune response. Fatty acid kinase is the only route for fatty acid
activation in Gram-positive pathogens and we will establish whether this two-component system uses a phospho-
cysteine intermediate in catalysis. X-ray crystallography and site-directed mutagenesis will define the structure
and mechanism of this unique kinase. Staphylococcus aureus fatty acid kinase is essential for cellular lipid
homeostasis and functions to re-cycle fatty acids into the phospholipid biosynthetic pathway. If fatty acids are
allowed to accumulate, they inhibit the activity of SaeS, a master regulator of virulence factor transcription. We
propose that cellular fatty acids arise from phospholipids, which serve as substrates in protein acylation and
secondary metabolite synthesis. Characterizing these pathways will lead to the identification of the essential
steps that enable the functionality of membrane lipoproteins and the virulence factor staphyloxanthin. A novel
lipidomics workflow was developed to determine the structure of S. aureus membrane phospholipid at the
infection site. This innovative approach will allow us to measure the extent of S. aureus utilization of host fatty
acids for membrane formation, and determine the roles for the genes responsible for fatty acid acquisition.
Streptococcus pneumoniae has a different lifestyle than S. aureus, and we will ascertain whether the number
and substrate selectivities of the fatty acid binding proteins determine the differences in the way S. aureus and
S. pneumoniae use host unsaturated fatty acids. This work is critical to understanding the mechanism of action
of new antibiotics entering human clinical trials, like afabicin (Debiopharm), which are designed to target
components of the bacterial fatty acid biosynthetic pathway. We discovered that S. aureus has an enzyme set
that actively metabolizes host unsaturated fatty acids to create a spectrum of oxygenated products. We also
found that S. aureus metabolizes prostaglandins. We will characterize the enzymes, transcriptional regulators
and efflux pumps responsible for the production and release of these new biological effectors into the host
environment. We will determine if these newly discovered pathways are a major countermeasure deployed by
S. aureus to combat antimicrobial fatty acids produced by the innate immune system. We will also determine
the structures of the S. aureus metabolites of host unsaturated fatty acids to verify that they are identical to gut
metabolites that signal the immune system to create a more tolerant environment for the bacteria. Accomplishing
these aims will define...

## Key facts

- **NIH application ID:** 9828779
- **Project number:** 5R01GM034496-36
- **Recipient organization:** ST. JUDE CHILDREN'S RESEARCH HOSPITAL
- **Principal Investigator:** Charles O Rock
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $723,024
- **Award type:** 5
- **Project period:** 1984-12-01 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9828779

## Citation

> US National Institutes of Health, RePORTER application 9828779, Regulation of lipid metabolism in bacteria (5R01GM034496-36). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9828779. Licensed CC0.

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