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

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.

Grant Number: 5R01AI160269-05
NIH Institute/Center: NIH
Principal Investigator: Steven Boyd