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 has completed Phase 1 clinical development in a fixed combination with the 4th generation cephalosporin Cefepime, and the combination will start Phase 3 pivotal trials in the second half of 2018. The VNRX-5133/cefepime 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).
This project has been funded in whole or in part with Federal funds from the National Institute for Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services, under Contract No. HHSN272201300019C, and Wellcome Trust under Award No. 360G-Wellcome-101999/Z/13/Z.
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.