A New Class of Broad-Spectrum Antibacterial Agents to Treat Multi-Drug Resistant Pathogens

Project Summary Cūrza is developing the CZ-02 platform of broad-spectrum antibiotics as a new class focusing on multidrug- resistant (MDR) Gram-negative pathogens that will also be efficacious against Gram-positive bacteria. CZ-02 antibacterials bind to a unique site on the bacterial ribosome that is not targeted by antibiotics available clinically which is expected to limit cross-resistance to other antibiotics. The initiation and subsequent development of the CZ-02 program represents a strong example for revisiting the use of natural products in drug discovery which has fallen out of favor in Pharma. CZ-02s were inspired by the natural product amicetin which selectively inhibits bacterial protein synthesis but suffers from limited antibacterial activity and poor drug-like properties. Careful engineering of the natural product has produced CZ-02s with exquisite selectivity for bacterial protein synthesis, potent antibacterial activity and excellent drug-like properties that have demonstrated efficacy against MDR pathogens in multiple animal models of infection while sparing mammalian cells from cytotoxicity. The goal of this Direct-to-Phase II project is to develop a new antibacterial drug candidate that covers Gram- negative pathogens found among Enterobacterales and the non-fermenters Acinetobacter baumanni and Pseudomonas aeruginosa as well as Gram-positive pathogens. The initial clinical indication will be for treating Urinary Tract Infections (UTIs), with other indications to follow (e.g. complicated intra-abdominal infections, pneumonia, bacteremia). At the conclusion of this Phase II SBIR will be a pre-clinical development candidate that is potent with broad spectrum activity that will be ready for Chemistry, Manufacturing and Controls (CMC) and toxicology/safety pharmacology under Good Laboratory Practices (GLP). Advancement of this antibacterial lead series will be accomplished by the following aims. Aim 1 will expand the spectrum of activity for advanced leads that have shown efficacy in UTI animal models with MDR Gram-negative pathogens. Curza’s proprietary model for producing potent and selective inhibitors of bacterial P-site protein synthesis, in combination with a battery of biological/biochemical activity assays (biochemical, microbiological, in vitro ADME-Tox), will be used for chemistry efforts to ensure compounds retain activity while expanding the spectrum of addressable pathogens to include A. baumannii and P. aeruginosa. Aim 2 will define pharmacokinetics (PK) while identifying the maximum tolerated dose and confirming efficacy by testing in thigh infection models to select CZ-02s for evaluation in UTI models. A lead and backup drug candidate will be selected in Aim 3 by evaluation in UTI models of antibiotic-resistant bacteria followed by non-GLP toxicology in rats to nominate a lead and backup. Aim 4 will scale-up production (non-GLP) to support in vivo studies while Aim 5 will establish the optimal dosing strategy from PK/Pharmacodynamic (PD) studies.