# Novel Cyclic Boronate Cell Wall Inhibitors Targeting Carbapenem-Resistant Acinetobacter baumannii

> **NIH NIH R44** · VENATORX PHARMACEUTICALS, INC. · 2024 · $1,000,000

## Abstract

PROJECT SUMMARY
β-lactams including carbapenems are the most widely used antibiotic class. Carbapenem-resistant A.
baumannii (CRAB) represents the most extreme resistant human pathogen among the Acinetobacter
species, where acquisition and evolution of β-lactamases have essentially eliminated all therapeutic
options. CRAB infections are classified by the US Centers for Disease Control and Prevention as an
“Urgent threat” and by the World Health Organization as a “Priority 1 critical threat”. To provide a new
therapeutic option against this prominent pathogen, Venatorx has identified a novel chemical series of
highly selective cyclic boronates that inhibit penicillin-binding proteins (PBPs) like β-lactams but that are
impervious to the action of all β-lactamases. This research program aims to deliver a cyclic boronate PBP
inhibitor (boro-PBPi) for the treatment of CRAB infections that exploits porin mediated uptake rather than
siderophore conjugation, in order to avoid both inactivation by β-lactamases and reduced activity through
loss of siderophore uptake as has been observed with cefiderocol (Fetroja®). Significant strides in
microbiological activity have been achieved with the lead boro-PBPi VNRX-14791 exhibiting an MIC90 of
16 µg/mL relative to 128/64 µg/mL for ampicillin-sulbactam and 64/4 µg/mL for sulbactam-durlobactam
against 26 CRAB clinical isolates. Prototype boro-PBPi VNRX-6884 was bactericidal in vitro and
achieved proof of concept efficacy in the murine thigh infection model in carbapenem-producing A.
baumannii while possessing favorable selectivity, ADME and PK properties. Optimization efforts
proposed herein target a 4-fold improvement in antibacterial activity to reach an MIC90 ≤4 µg/mL, driven
by rational structure-guided design for AbPBP3 affinity as well as using specific physicochemical
properties to improve cellular accumulation in gram-negative bacteria. As contingency, we will also
explore optimization of inhibitors that target both AbPBP2 and AbPBP3 using a recently identified starting
point (VNRX-14841) to enhance efficacy in vivo through dual inhibition AbPBP2 and AbPBP3 that
function in the elongasome and divisome, respectively. Such an optimized boro-PBPi will be a first new
class antibiotic addressing resistance to β-lactams for the treatment of CRAB infections and a long-term
therapeutic solution to resistance development in A. baumannii.

## Key facts

- **NIH application ID:** 10918437
- **Project number:** 1R44AI181353-01A1
- **Recipient organization:** VENATORX PHARMACEUTICALS, INC.
- **Principal Investigator:** Tsuyoshi Uehara
- **Activity code:** R44 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $1,000,000
- **Award type:** 1
- **Project period:** 2024-04-01 → 2027-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10918437

## Citation

> US National Institutes of Health, RePORTER application 10918437, Novel Cyclic Boronate Cell Wall Inhibitors Targeting Carbapenem-Resistant Acinetobacter baumannii (1R44AI181353-01A1). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10918437. Licensed CC0.

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