# Novel cyclic boronate Penicillin Binding Protein Inhibitors to eliminate the threat posed by β-lactamases and enable a future treatment option for carbapenem-resistant Enterobacterales infections > **NIH NIH R01** · VENATORX PHARMACEUTICALS, INC. · 2024 · $1,220,775 ## Abstract PROJECT SUMMARY Carbapenem-resistance in Enterobacterales has steadily increased over the past decade, leading to multidrug and pan-drug resistance (MDR/PDR), further emphasizing the need for new innovative therapies. Carbapenem- resistant Enterobacterales (CRE) is a serious global health problem 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”. The β-lactams have long been the front line therapeutic option for such infections, but efficacy of these agents, including last resort carbapenems, is threatened by recent expansion of β-lactamases, particularly subtypes (e.g., NDM) spreading rapidly among Enterobacterales that are unaffected by clinically-available β-lactam/β- lactamase inhibitor combinations. To address the medical need, Venatorx has identified a novel series of highly selective cyclic boronates that bind to and disrupt penicillin-binding protein (PBP) transpeptidase (TPase) function while avoiding the action of all current and future β-lactamases. This approach creates the first prospect and “rare” new class gram negative agent to treat infections caused by any β-lactamase-producing CRE pathogen. Significant strides in microbiological activity have already been achieved within the series by the lead compound VNRX-6736, with an MIC90 of 32 µg/mL relative to 128 µg/mL for meropenem-vaborbactam and ≥1,024 µg/mL for ceftazidime-avibactam in a recent challenge set of 100 CRE isolates. Not only does VNRX- 6736 outperform these clinical comparators from an MIC90 perspective, but does so with a narrow range of MIC owing to β-lactamase avoidance, a feature that will ultimately benefit setting of breakpoints. The series is rapidly bactericidal, exhibits a low spontaneous mutational frequency (frequency of resistance at 4x MIC of <2.7 x 10-11 in E. coli ATCC 25922) and has favorable ADME and PK properties. Proof of concept efficacy has been achieved by VNRX-6736 in the murine thigh model of carbapenem-resistant E. coli infection and pharmacokinetics modeling suggests that 30-45% time above MIC is required to achieve efficacy. Optimization efforts proposed herein are targeting an 8-fold improvement in antibacterial activity driven by rational structure-guided design to improve PBP binding interaction kinetics to enable an MIC90 ≤ 4 µg/mL. Such an optimized cyclic boronate PBPi could be a 1st new class antibiotic addressing resistance to β-lactams for the treatment of infections caused by CRE and a long term therapeutic solution to resistance development in Enterobacterales. ## Key facts - **NIH application ID:** 10833602 - **Project number:** 5R01AI160269-04 - **Recipient organization:** VENATORX PHARMACEUTICALS, INC. - **Principal Investigator:** Steven Armen Boyd - **Activity code:** R01 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $1,220,775 - **Award type:** 5 - **Project period:** 2021-05-04 → 2026-04-30 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10833602 ## Citation > US National Institutes of Health, RePORTER application 10833602, Novel cyclic boronate Penicillin Binding Protein Inhibitors to eliminate the threat posed by β-lactamases and enable a future treatment option for carbapenem-resistant Enterobacterales infections (5R01AI160269-04). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10833602. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*