# Molecular mechanism of cephalosporin resistance of N. gonorrhoeae conferred by mutated PBP2

> **NIH NIH R01** · UNIVERSITY OF SOUTH ALABAMA · 2022 · $728,298

## Abstract

Project Summary
 Neisseria gonorrhoeae, the causative agent for the sexually transmitted infection gonorrhea, is
responsible for over 800,000 infections annually in the U.S. and 78 million cases worldwide. Untreated or
untreatable infections can lead to infertility, pelvic inflammatory disease (PID) in females, gonococcal arthritis
in both sexes, and an increased risk of both contracting and transmitting HIV. Over the past several decades,
the inexorable increase of resistance in this organism toward multiple classes of antibiotics has severely limited
treatment options for gonococcal infections. Most alarmingly, resistance against the extended-spectrum
cephalosporin (ESC) ceftriaxone poses a serious threat to public health. This situation requires an
understanding of antibiotic resistance at the molecular level in order to enable design of new antimicrobials.
 ESC resistance of N. gonorrhoeae is conferred by mutated forms of penicillin-binding protein 2 (PBP2).
In this application, we propose to elucidate the molecular mechanism of resistance, with the overarching
hypothesis that mutations in PBP2 restrict the molecular dynamics of the protein. It builds upon our recent
understanding of the interactions made by wild-type PBP2 when bound by ESCs and how conformational
changes associated with binding and acylation appear restricted in PBP2 derived from ESCR strains. The
investigation comprises three aims: Specific Aim 1 is a structure-function analysis of wild-type PBP2 to
investigate the importance of specific interactions formed when PBP2 is bound and acylated by
cephalosporins. In Specific Aim 2, we will elucidate how key mutations present in PBP2 from ESCR strains of
N. gonorrhoeae reduce inactivation by cephalosporins while retaining sufficient biological function to support
growth of the organism. Finally, Specific Aim 3 will examine the behavior of PBP2 variants in solution to
determine whether mutations hinder protein dynamics. By revealing the molecular mechanisms of how
mutations in PBP2 overcome the lethal action of β-lactams, these investigations will enable new strategies for
the development of replacement anti-gonococcal agents.

## Key facts

- **NIH application ID:** 10467153
- **Project number:** 1R01AI164794-01A1
- **Recipient organization:** UNIVERSITY OF SOUTH ALABAMA
- **Principal Investigator:** Christopher Davies
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $728,298
- **Award type:** 1
- **Project period:** 2022-03-10 → 2027-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10467153

## Citation

> US National Institutes of Health, RePORTER application 10467153, Molecular mechanism of cephalosporin resistance of N. gonorrhoeae conferred by mutated PBP2 (1R01AI164794-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10467153. Licensed CC0.

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