The novel antimicrobial resistance breaker and MBL/SBL inhibitor APC247 - studies on mechanism of action (MoA) and resistance development.

The development of antibiotic resistance is one of the major global health challenges in the fight against infectious diseases. Adjutec Pharma AS is a newly started company (2019) that develops drugs that restore the effectiveness of certain types of antibiotics called carbapenems, which are one of our most modern antibiotics. Carbapenems are a last-resort antibiotic that is used when no other antibiotic has an effect. Unfortunately, bacteria have developed methods to break down carbapenems. Carbapenemases are a type of bacterial beta-lactamase enzymes and occur in two classes, metallo-beta-lactamases (MBL) and serine-beta-lactamases (SBL). These destroy carbapenems and provide resistance to these drugs in a number of potentially fatal bacterial infections. With the OMNImere project, a completely new treatment principle has been identified in that one of our substances inhibits both the MBL and SBL enzymes very effectively in the bacteria that are on the World Health Organization (WHO) list of highly dangerous resistant bacteria: Klebsiella pneumoniae (no. 1), Escherichia coli (no. 2) and Acinetobacter baumannii (no. 3). This is unique in today's development of new resistance inhibitors. In the OMNImere project, we are investigating a new combination product that consists of a drug (beta-lactam antibiotics) and our new invention, a new type of inhibitor (APC247) in synergy. We have seen that APC247 restores the effect of several antibiotic drugs in the bacteria Klebsiella and E. coli. We have mapped the mechanism of action of APC247 in relation to other relevant beta-lactamase inhibitors on the market, and found that APC247 acts on more resistance mechanisms than other similar inhibitors on the market. The most important challenges in the project are a) to evaluate the mechanism of action in the bacteria for APC247, and b) to investigate whether resistance to the combination of antibiotic and inhibitor can occur, and to investigate which possible resistance mechanisms arise. In this project, we collaborate with advanced research groups on antibiotic resistance at the University of Oslo and the University of Tromsø. Preliminary microbiological studies show that the APC247-carbapenem combination is effective against a range of pathogenic bacteria.