# Identification of the factors contributing to resistance of Group A Streptococcus to human group IIA secreted phospholipase A2

> **NIH NIH R21** · UNIVERSITY OF KENTUCKY · 2020 · $232,141

## Abstract

Human Group IIA secreted phospholipase A2 (hGIIA) is a highly cationic small protein!
important for the innate immune defense against Gram-positive bacteria. The enzyme traverses
the thick peptidoglycan layer of Gram-positive bacteria to reach the phospholipid membrane
where it catalyzes the hydrolysis of phosphatidylglycerol, ultimately leading to bacterial death
through lysis. In comparison to other Gram-positive bacteria, Group A Streptococcus (GAS), or
Streptococcus pyogenes is remarkably resistant to hGIIA activity. GAS transposon library
screens, designed to identify the genes that provide susceptibility/resistance to hGIIA,
uncovered a number of genes involved in biosynthesis and modification of Lancefield group A
carbohydrate (GAC) and lipoteichoic acid (LTA), two crucial cell envelope constituents of GAS.
GAC is a rhamnose-containing glycopolymer covalently attached to peptidoglycan. Modification
of GAC with negatively charged glycerol phosphate as well as the absence of positively-charged
D-alanine modifications in LTA drastically compromise GAS survival when challenged with
hGIIA. This project seeks to identify the functions of two previously uncharacterized proteins
identified by an hGIIA sensitivity screen, a putative GAC hydrolase, GacM, and a GT-C type
membrane glycosyltransferase, PgtC. Additionally, we uncovered a GT-A type membrane
glycosyltrasferase PgtA that might participate together with PgtC in a protein glycosylation
pathway in GAS. We will define the biological functions of these three proteins and their roles in
antimicrobial resistance and virulence using a range of genetic, biochemical and analytical
approaches. Functional characterization of these novel targets will lead to an increased
understanding of how antimicrobial resistance is regulated in all Gram-positive bacteria and how
resistance to antimicrobials is emerging among Gram-positive pathogens.

## Key facts

- **NIH application ID:** 9877445
- **Project number:** 1R21AI149366-01
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Natalia Korotkova
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $232,141
- **Award type:** 1
- **Project period:** 2020-04-06 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9877445

## Citation

> US National Institutes of Health, RePORTER application 9877445, Identification of the factors contributing to resistance of Group A Streptococcus to human group IIA secreted phospholipase A2 (1R21AI149366-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9877445. Licensed CC0.

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