Bacteria have developed resistance to beta-lactam (BL) antibiotics by producing beta-lactamase enzymes, which catalytically inactivate BL antibiotics. Today, over 70% of hospital-based infections caused by gram-negative bacteria are associated with an antibiotic resistant organism.1 To overcome this kind of resistance, BL antibiotics have been successfully combined in the past with beta-lactamase inhibitors (BLI) (Amoxicillin/Clavulanic acid, Piperacillin/Tazobactam). Unfortunately, the suite of existing BLIs are not sufficiently broad in their effectiveness against the extended spectrum beta-lactamases (ESBLs) and different subtypes of carbapenem-hydrolyzing beta-lactamases (carbapenemases), including against the superbugs that express NDM and VIM metallo-beta-lactamases.
A new injectable broad-spectrum -lactamase inhibitor (BLI) with activity against all of the major sub-classes of beta-lactamases, including both the well-established serine beta-lactamases and the emerging metallo-beta-lactamases. VNRX-5133 is currently completing Phase 1 clinical development in combination with a clinically validated broad spectrum beta-lactam partner, and the combination will start Phase 2/3 registration clinical trials in 2018. The VNRX-5133/BL combination has the potential to be best-in-class against multi-drug resistant (MDR) gram-negative bacterial infections, including Carbapenem-resistant Enterobacteriaceae (CRE) and Carbapenem-resistant Pseudomonas aeruginosa (CR-PA). Preclinical and Phase 1 development have been financially supported by NIAID (BAA# HHSN27220130019C) and Wellcome Trust.
A novel broad-spectrum orally-bioavailable BLI, with potent activity against both ESBLs and serine carbapenemases. Oral treatments effective also against multi-drug-resistant gram-negative bacteria are urgently needed so that patients can be discharged more quickly from the hospital and continue the therapy at home, or avoid hospitalization altogether. Preclinical and Phase 1 development are financially supported by NIAID (BAA# HHSN272201600029C).
Novel Anti-Bacterial Programs
VenatoRx is developing a novel class of non-beta-lactam molecules that kill bacteria by the same selective mechanism as BLs: blocking cell wall synthesis via binding to the bacterial penicillin binding proteins (PBPs). Chemically distinct from the BLs, these new molecules have been designed to be impervious to degradation by any beta-lactamases. By circumventing over seventy years of beta-lactamase-driven resistance, this new class of PBP inhibitors has the potential to usher in a new wave of antibacterial therapeutics. CARB-X and DTRA (HDTRA117C0070) are providing financial support for the development of this platform.