# BLRD Research Career Scientist Award Application

> **NIH VA IK6** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2023 · —

## Abstract

The overall research program of the applicant has focused on the role of LOS and the innate immune
system and has shown that the degree of phosphorylation of the lipid A component is correlated with the
potential of the LOS to induce innate immune cytokine-mediated inflammation and, in general, with the severity
of Neisserial disease. Based on the results of these studies, recent work has undertaken the development of
potential therapeutics targeting gonococcal LOS as infections due to N. gonorrhoeae are a major cause of
morbidity with an estimated 850,000 cases in the U.S. and 87 million cases worldwide annually. Within the VA
Health Care System, cases of gonorrhea increased between 2013 and 2017 with the total number in that time
period at 10,587. Within the U.S. military, service members are a defined high-risk group for gonorrhea as
noted by the U.S. Preventive Services Task Force as the high-risk environment of active military service is
thought to increase risky behavior and, thus, the rate of sexually transmitted infections including gonorrhea. A
total of 27,658 cases of gonorrhea were identified among active duty personnel during FY 2007 to 2015 (222.7
per 100,000 military compared with 179.3 per 100,000 non-military in 2018). There is no vaccine to N.
gonorrhoeae and a great need for new antibiotics due to the alarming rise in multidrug-resistance (MDR),
which is making emergence of untreatable gonococcal infections a real prospect. Thus, there is a compelling
need for new antimicrobials for gonococcal infections.
 To this end, the projects to be pursued during the proposed funding period of this SRCS award are as
follows: 1) LpxC inhibitors and cell-penetrating peptides; we recently reported that treatment of gonococci
with an inhibitor of LpxC, the enzyme that catalyzes the second step of lipid A biosynthesis, was bactericidal
for MDR and human challenge strains of gonococci and reduced cytokine induction without apparent human
cell cytotoxicity. Most recently, we evaluated the bactericidal potential of a 12 amino acid cell-penetrating
peptide (CPP) and found that it penetrated the bacterial membrane and was bactericidal for all multi-drug
resistant and human challenge strains of gonococci tested and reduced inflammatory cytokine induction and
prevented bacterial cell invasion of cervical epithelial cells. These novel data highlight LpxC inhibitors and
CPP as promising antimicrobials for N. gonorrhoeae and strongly support the hypothesis of this application that
inhibiting the biosynthesis of lipid A components with LpxC inhibitors and disrupting outer membrane integrity
with CPP will impact bacterial viability and host response to N. gonorrhoeae infection in vitro and in vivo, which
will have a therapeutic impact on infection outcomes. Translational studies of these two potential therapeutics
for gonorrhea will be the primary focus of the investigations proposed for the award period. 2) EptA
inhibitors; we will continue our collaborat...

## Key facts

- **NIH application ID:** 10512756
- **Project number:** 5IK6BX005798-02
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** Gary A Jarvis
- **Activity code:** IK6 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2023
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2021-10-01 → 2026-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10512756

## Citation

> US National Institutes of Health, RePORTER application 10512756, BLRD Research Career Scientist Award Application (5IK6BX005798-02). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10512756. Licensed CC0.

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