# Mechanisms of resistance against the human group IIA secreted phospholipase A2 in Group B Streptococcus

> **NIH NIH R21** · UNIVERSITY OF KENTUCKY · 2021 · $180,759

## Abstract

Antimicrobial peptides play a major role in humoral innate immunity against microorganisms.
Multiple in vivo and in vitro studies highlight the important function of human group IIA secreted
phospholipase A2 (hGIIA) in protection against Gram-positive bacterial infection including Group
B Streptococcus (GBS), a leading cause of neonatal sepsis and meningitis. hGIIA kills bacteria
by catalyzing the hydrolysis of the membrane glycerophospholipids. The Gram-positive cell
envelope, consisting of multiple peptidoglycan layers decorated with a variety of glycopolymers,
represents a substantial barrier to hGIIA and it is poorly understood how hGIIA gains access to
the bacterial plasma membrane to produce lethal damage. We have recently identified novel
bacterial resistance mechanisms against hGIIA in the bacterium closely-related to GBS, Group
A Streptococcus (GAS). Our work revised the current models of GAS cell wall architecture and
highlighted the importance of these structural determinants for resistance to hGIIA. Interestingly,
GBS is killed by hGIIA at concentrations that are approximately 500-fold lower, than the GAS
strains. The experiments described in this proposal are designed to understand the underlying
mechanisms for hGIIA potency against GBS. To accomplish our goal, we will use two
approaches. In the first approach we will conduct screens of a recently constructed, highly
saturated GBS transposon mutant library using lethal and sub-lethal concentrations of hGIIA.
After construction of deletion mutants in the identified genes we will perform antimicrobial and
mechanistic assays and transmission electron microscopy analysis of the freeze-substituted
cells to confirm the hGIIA susceptibility phenotype of the mutants and understand the
mechanisms of resistance/susceptibility. In the second approach, we will investigate the role of
the major peptidoglycan-attached glycopolymer of GBS, the Group B Carbohydrate (GBC), in
hGIIA susceptibility by swapping GBC with the GAS cell wall glycopolymer in GBS. Successful
outcomes will guide future efforts for new drug development against GBS.

## Key facts

- **NIH application ID:** 10145585
- **Project number:** 5R21AI146945-02
- **Recipient organization:** UNIVERSITY OF KENTUCKY
- **Principal Investigator:** Natalia Korotkova
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $180,759
- **Award type:** 5
- **Project period:** 2020-04-15 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10145585

## Citation

> US National Institutes of Health, RePORTER application 10145585, Mechanisms of resistance against the human group IIA secreted phospholipase A2 in Group B Streptococcus (5R21AI146945-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10145585. Licensed CC0.

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