ZinChel: combating antibiotic resistance - hit to lead development of a new metallo-beta-lactamase inhibitor

Antibiotic resistance is one of the biggest global threats to health today. The Infectious Disease Society of America (IDSA) already designated antimicrobial resistance in 2011 as the biggest health threat to humanity. An established strategy for combating antimicrobial resistance (AMR) is to use a combination of antibiotics together with an inhibitor of resistance (referred to herein as adjuvants) that interact with known antibiotics, in such a way that the effect of antibiotics is enhanced. Through a fruitful collaboration between the research group of Professor Pål Rongved, UiO, Pharmaceutical Institute and Professor Ørjan Samuelsen, the head of the K-res Center at the University Hospital in Northern Norway (UNN), a new class of adjuvants has been produced that significantly enhances the effects of antibiotics against threatening resistant Gram-negative bacteria. This work has been funded by the Research Council of Norway BIOTEK2021 Program (optimization) in the period 2015-2017. In addition, the work has received significant support from Novo Seeds (funds without obligations). The very good results have been widely discussed in media in Norway and abroad. By screening of approx. 250 new adjuvants showed approx. 50 highly promising antimicrobial activity in combination with antibiotics. Among the 50 promising adjuvants, 3-5 are selected as lead candidates, one of which is particularly promising. The project received FORNY grant In 2017, the funds will finance the necessary preclinical documentation of these 3-5 adjuvants and finance the commercialization of this technology. In this FORNY project, the goal is to build relevant preclinical data, which holds industry standards, to attract industrial investors. There has already been a request from several key players in the pharmaceutical industry. We will choose which commercial strategy to follow, depending on the development of the project, and the attention from the investors.

We are applying for financial support to develop a new combination drug for the treatment of Gram-negative bacteria. The novelty is based on a new class of metallo-beta-lactamase inhibitors we have termed ZinChel. The aim of the project is to either: (i) build a documentation package sufficient to license our project to the pharmaceutical industry, or (ii) to build a documentation package sufficient to receive FORNY support from the research council and launch a startup company together with Inven2. At present, three promising compounds have been identified which overcome bacterial resistance when used as adjuvants with established beta-lactam antibiotics on the market. The most promising ZinChel compound demonstrated a strong ability to restore the antimicrobial effect of the last resort carbapenem antibiotic Merrem® I.V. (meropenem for injection) when tested against a number of otherwise meropenem-resistant, clinically relevant bacterial isolates harboring metallo-beta-lactamases. This proposal will cover the development of these initial hits into a lead candidate up to preclinical studies. Prior art analyses indicate that the idea and anticipated mechanism of action is novel. We are planning to generate extensive physicochemical, microbiological and modeled pharmacodynamics data on our most promising compounds. We will study the potential for resistance development and mechanism of action. In parallel, an IPR platform will be established based on the previously filed priority patent application.