# Antimicrobial mechanisms of Specialized Proresolving Medicators

> **NIH NIH R01** · ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED · 2022 · $402,500

## Abstract

Project summary
Despite advances in antibiotic therapy, there is a significant need for more efficacious treatments of severe
bacterial infections. The host responds to bacterial infection by activating the innate immune system to clear
pathogen by phagocytic and killing mechanisms, resolve inflammation and return to homeostasis. In sepsis,
activation of host response causes massive inflammation as well as a later paradoxical dysregulated
inflammatory response where the host is immunocompromised and is susceptible to secondary infections.
 Specialized Pro-resolving Mediators (SPMs) are endogenously produced lipid mediators with infection
resolution activity. A recent report showed that there was a temporal difference in release of different SPMs
where early increase of Resolvins (Rvs) was associated with infection resolution. We and others show that
SPMs, such as Lipoxin A4 (LXA4), and Rvs increased survival, decreased systemic inflammatory response and
reduced bacteria load in cecal ligation and puncture (CLP) sepsis or other models of bacterial infection. We
obtained evidence that LXA4 increased Fcγ receptor1 (FcγR1) dependent neutrophil phagocytic ability in CLP-
sepsis while Rvs D1 and D2 increased human monocyte phagocytosis of Pseudomonas aeruginosa (P.
aeruginosa) suggesting that SPMs can promote host defense to clear pathogen in sepsis.
 Quorum sensing is a cell density dependent mechanism which regulates expression and release of
bacterial virulence factors. We have evidence that LXA4 inhibits binding of the bacterial quorum sensor 3-oxo-
C12 HSL in P. aeruginosa with a potency approximately 1000-fold greater than known quorum sensing inhibitors.
LXA4 reduced release of the exotoxin - pyocyanin which suggests that LXA4 may reduce bacterial virulence by
quorum sensing inhibition. This is the first evidence that an endogenously produced compound can both
augment host defense and directly reduce bacterial virulence.
 Therefore, we hypothesize that SPMs promote infection resolution by enhancing host defense and
reducing bacterial virulence. 3 Specific Aims are proposed. In AIM 1 we will test the hypothesis that SPMs
enhance host defense to resolve infection in the 2-hit model of CLP sepsis with secondary Pseudomonas lung
infection. In AIM 2 we will test the hypothesis that the cellular mechanism of SPM enhanced antimicrobial
leukocyte function is by promoting activity Rho GTPases and differentiation of monocytes to a pro-resolution
phenotype. In AIM 3 we will determine if SPMs inhibit quorum sensing and reduce bacterial virulence. We believe
investigation of SPM mediated mechanisms of antimicrobial activity may have broad applications in bacterial
infections and may contribute to new treatments.

## Key facts

- **NIH application ID:** 10405100
- **Project number:** 5R01AI128202-05
- **Recipient organization:** ROWAN UNIVERSITY SCHOOL/OSTEOPATHIC MED
- **Principal Investigator:** KINGSLEY E YIN
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2018-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10405100

## Citation

> US National Institutes of Health, RePORTER application 10405100, Antimicrobial mechanisms of Specialized Proresolving Medicators (5R01AI128202-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10405100. Licensed CC0.

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