# New class of PBP inhibitors to address PBP2-mediated resistance in Neisseria gonorrhoeae

> **NIH NIH R01** · VENATORX PHARMACEUTICALS, INC. · 2022 · $1,579,751

## Abstract

PROJECT SUMMARY
Multidrug resistant-gonorrhea is a serious global health threat. Penicillin Binding Protein-targeting β-lactams
have long been the front line therapeutic option for gonorrhea, but are now in serious jeopardy. Resistance to
the last remaining front line β-lactams, the extended spectrum cephalosporins, has steadily increased over the
past decades resulting in the CDC eliminating cefixime as a therapeutic option in 2012. Now only ceftriaxone
remains, but a series of resistant clinical isolates exhibiting PBP2-target based resistance have emerged in the
past decade, forecasting its imminent failure. As few clinical development candidates addressing MDR-
gonorrhea are in the drug development pipeline, and vaccine development is unlikely to be a solution due to high
antigenic variability in clinical isolates, there is an urgent need for new therapeutic options. A new chemical
series maintaining PBP target inhibition represents a promising strategy, enabling new combination therapies to
minimize further evolution of resistance. VenatoRx has identified a novel chemical series of reversible covalent
non-β-lactam Penicillin Binding Protein inhibitors impervious to the action of β-lactamases that are being
optimized to address altered PBP2 targets responsible for ESC-resistance in Neisseria gonorrhoeae. Significant
strides in microbiological activity have been achieved with the lead compound VNRX-6355 in MDR-gonorrhea
isolates including a mosaic PBP2-producing H041 clinical isolate. Improved binding to altered PBP2 variants by
VNRX-6355 has provided a >128-fold improvement in microbiological activity in H041 over initial hit compounds
in the series (shift in MIC from >512 mg/L to 4 mg/L) and is only 8-fold away from our MIC target to obtain an
MIC90 of ≤0.5 mg/L. These compounds are highly selective, rapidly bactericidal and efficacious in a murine
septicemia model of E. coli infection. The goal of this proposal is to select a potent preclinical candidate
addressing PBP2 target variants in ESC-resistant gonorrhea, confirm favorable PK properties for intramuscular
administration, select the first preclinical development candidate, perform preclinical IND-enabling studies and
file an IND with the US FDA. Ultimately this approach is intended to be a long term strategy to safeguard PBP-
targeting in gonorrhea treatment by preventing the expansion of β-lactamases in Neisseria gonorrhoeae that
would inevitably evolve from more effective targeting of PBP2 variants by current or newly optimized β-lactam-
based strategies.

## Key facts

- **NIH application ID:** 10459332
- **Project number:** 5R01AI141239-04
- **Recipient organization:** VENATORX PHARMACEUTICALS, INC.
- **Principal Investigator:** Denis Marc Daigle
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $1,579,751
- **Award type:** 5
- **Project period:** 2019-09-05 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10459332

## Citation

> US National Institutes of Health, RePORTER application 10459332, New class of PBP inhibitors to address PBP2-mediated resistance in Neisseria gonorrhoeae (5R01AI141239-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10459332. Licensed CC0.

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