# Controlling bactermic pneumococcal pneumonia with synthetic dominant-negative competence peptides

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2020 · $501,281

## Abstract

Project Summary
Community-acquired pneumonia (CAP) is a significant cause of morbidity and mortality in patients of all ages,
particularly the elderly. Streptococcus pneumoniae (pneumococcus) is a major cause of CAP. During CAP,
pneumococcus releases pneumolysin (PLY) and cell wall components, which disrupt alveolar-capillary barrier.
Pneumococcus invades bloodstream through the eroded vascular endothelium, causing bacteremia and sepsis
in 25-30% of patients, with 5-7% fatality. Other complications include multi-organ dysfunction, empyema,
respiratory failure, pericarditis, and adverse cardiac events. Regretfully, little is known about how pneumococcus
regulates the release of PLY and cell wall components that disrupt alveolar-capillary barrier. Our long-term goal
is to device effective therapy against pneumococcal infection. The immediate objectives of this proposal are to
elucidate the role of competence-regulated allolyis in breaching the air-blood barrier and devise effective
measures to thwart bacteremia and sepsis. Preliminarily, we have shown that induction of ComX, the master
regulator of competence regulon by the competence stimulating pheromone peptide (CSP), upregulates the
expression of allolytic enzymes LytA, CbpD and CibAB. Allolysis substantially enhances the release of PLY, and
ultimately, facilitates pneumococcal escape from infected lung to cause systemic bacteremia. Worse yet,
fluoroquinolone and clavulanate antibiotics widely prescribed to treat pneumococcal infection are capable of
activating ComX-dependent allolysis. Significantly, we have synthesized dominant-negative competence
stimulating peptides (dnCSPs) and shown they competitively inhibit the induction of ComX-dependent allolysis,
PLY release and hemolysis, and reduce mouse mortality during bacteremic pneumonia. We propose 3 Specific
Aims to test the hypothesis that dnCSPs will be effective in inhibiting the ComX-regulated allolysis during
bacteremic pneumonia. In Aim 1, chemical synthesis and structural analysis will be used to derive the next
generation high potency dnCSPs that will inhibit ComX-regulated allolysis. Then, both wild-type and dnCSPs will
be utilized to identify the key structural features in CSP that are involved in both binding and activating of the
histidine kinase receptor ComD. In Aim 2, we will examine if ComX-induced allolytic release of PLY and cell wall
components during bacteremic pneumococcal pneumonia—in the presence or absence of treatment with
fluoroquinolones—lead to air-blood barrier disruption, sepsis, and lung and cardiac dysfunction in mice. In Aim
3, we will determine the efficacy of dnCSPs in attenuating air-blood barrier disruption, bacteremic pneumonia
and sepsis, and lung and cardiac dysfunction in mouse model of pneumococcal infection, in the presence or
absence of fluoroquinolone treatment. Completion of the proposal will chart new path to treat pneumococcal
infection by targeting the competence regulon.

## Key facts

- **NIH application ID:** 9893021
- **Project number:** 5R01HL142626-02
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Gee W Lau
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $501,281
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9893021

## Citation

> US National Institutes of Health, RePORTER application 9893021, Controlling bactermic pneumococcal pneumonia with synthetic dominant-negative competence peptides (5R01HL142626-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9893021. Licensed CC0.

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