TECHNOLOGY

Curza is a small-molecule therapeutics company that has developed several structurally distinct classes of proprietary drugs focused on infectious diseases and oncology.  

Curza's lead program (CZ-02) is a new class of broad spectrum antibiotics, focused on ESKAPE pathogens, with a focus on drug-resistant Gram-negative bacteria.  Inspired by a natural product, this class targets an unexploited binding site of the bacterial ribosome.  With ever increasing reports of resistance to frontline therapies addressing Gram-negative bacteria, there is a critical need for new therapies that work in new ways.  However, very little can be found in the development pipeline.  As a result, Curza's compounds are addressing a major unmet medical need.

A viable approach to discover new therapeutic leads is re-evaluation of existing, but under-scrutinized classes of natural products.  Through this approach, a natural product scaffold was identified as a lead for a program directed towards antibiotics for tuberculosis.  Initial evaluation of activity against other bacteria indicated that the antibacterial spectrum was limited to Mycobacterium spp.  However, based on the chemical structure and related compounds, we expected to be able to generate analogs with more broad spectrum activity.

The structure of the natural product and two analogs bound to the ribosome were solved and revealed binding to a highly conserved region of the peptidyl transferase center (PTC) in a manner that appears to convey prokaryotic selectivity.  This newly discovered binding site represents a new mechanism of action directed at one of the most validated antibiotic targets – the ribosome.  Importantly, this binding modality has not been exploited in current therapeutics.  Targeting this highly conserved region is expected to lead to slow rates of resistance.

Curza's lead optimization has produced a new series of CZ-02 compounds that have expanded the antibacterial spectrum of activity from solely Mycobacterium tuberculosis to include potent activity against ESKAPE pathogens, including drug-resistant strains.  These analogs inhibit protein synthesis in the nM concentration range, exhibit selectivity indexes of up to 1,000 for inhibition of bacterial versus mammalian protein synthesis and have very limited toxicity to mammalian cells.

Curza's newest CZ-02 compounds continue to demonstrate excellent activity against Mtb.  Importantly, they are active against virulent and MDR-Mtb strains, under anaerobic conditions, are bactericidal and are active against intracellular Mtb demonstrating that CZ-02 compounds penetrate mammalian THP-1 monocytes which is ultimately important for the treating of tuberculosis infections.

While the primary focus of the CZ-02 program is Gram-negative pathogens, there will always be a need to address Gram-positive organisms given the continual battle of humans vs. Bacteria.  CZ-02 compounds are being developed to exhibit high-level potency against Gram-positive superbugs such as methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Enterococcus (VRE).