# Chemical Biological Discovery of Lipid Virulence Factors in the Major Bacterial Pathogens

> **NIH NIH R01** · BRIGHAM AND WOMEN'S HOSPITAL · 2024 · $586,376

## Abstract

Project Summary
Chemical Biological Discovery of Lipid Virulence Factors in the Major Bacterial Pathogens
For decades, the search for the causes of bacterial virulence has focused on genes rather than metabolites.
Genetic approaches have been broadly successful, and modern infectious disease research relies
fundamentally on genomic maps of the major pathogens. Owing to the lack of whole-organism chemical
biology tools, bacterial lipids have not been systematically tested for their roles in virulence, even though lipids
are the primary interface with the human host, where they control nutrient flow and trigger host immune
response. We invented a mass spectrometry platform for lipid profiling to detect nearly all ionizable lipids in a
bacterial cell within 2 hours. Experiments on Mycobacterium tuberculosis and Salmonella enterica serovar
Typhi now provide clear evidence for the general insight that many, perhaps the majority, of lipids in the world's
bacterial pathogens, are currently unknown as named compounds. Based on successes in identifying virulence
factors in two major pathogens of worldwide significance, we will carry out a chemical biology approach known
as forward lipidomics. Specifically, we will use whole organism mass spectrometry profiling to discover the
lipids that are selectively expressed in virulent bacteria and are unknown in existing lipid catalogs. Then, we
will chemically synthesize the virulence associated lipids and link them to their biosynthetic genes for deletion
in bacteria using reverse genetic approaches. Using genetically modified bacteria that are deficient in defined
lipids, we will determine the roles of virulence lipids during infection. Using nature identical synthetic lipids, we
will determine the cellular mechanisms of generation of foamy macrophages and identify immune receptors
that mediate host response. We will create lipid maps of the major Gram negative pathogen groups based on
patient strains to build the overlooked field of chemical biology of bacterial virulence. These basic and
translational studies will support the development new forward lipidomics approaches to the diagnosis and
treatment of major infectious diseases.

## Key facts

- **NIH application ID:** 10845289
- **Project number:** 5R01AI165573-03
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** DAVID Branch MOODY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $586,376
- **Award type:** 5
- **Project period:** 2022-06-22 → 2025-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10845289

## Citation

> US National Institutes of Health, RePORTER application 10845289, Chemical Biological Discovery of Lipid Virulence Factors in the Major Bacterial Pathogens (5R01AI165573-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10845289. Licensed CC0.

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