The World Health Organization (WHO) has declared antimicrobial resistance (AMR) as one of the top 10 global public health threats facing humanity. WHO has called for the urgent development of new treatment solutions to infections with multidrug-resistant Gram-negative bacteria, notably from carbapenem-resistant isolates of Pseudomonas aeruginosa, Acinetobacter baumannii, or Enterobacteriales such as e.g. Klebsiella pneumonia and Escherichia coli. One common resistance mechanism that is of major clinical importance is that caused by metal-beta-lactamases, enzymes which are dependent on zinc for their function (action). Better antimicrobial stewardship, and new diagnostics and therapy options are in general desperately needed. This project thus targets an unmet medical need, as no inhibitor of metallo-beta-lactamase enzymes is presently available commercially. The company AdjuTec Pharma has developed a set of zinc-chelating inhibitor compounds targeting the metal-beta-lactamase enzymes, among which are APC148, the primary lead candidate. In this project the Bacterial Evolution and Disease group (BadBugs) works to determine the frequency and mechanism of resistance development to the compound (FoR and MoR, respectively), as well as to delineate in detail the mechanism of action (MOA) of the APC148 compound, and how it interacts with the target metallo-beta-lactamase enzymes. The pre-clinical development phase will be complete during the fall of 2023.
The project is tightly connected to (and integrated with) the "Antimicrobial resistance breaker" project hosted by the MicroPath group.
Funding:
The project is funded by an innovation programme grant through the Research Council of Norway (IPN grant).