Beta-Lactamase Inhibitors Synthesised through in Situ click chemistry

Herein, kinetic-guided target synthesis (KTGS) will be used to discover novel boronic acids inhibitors of KPC-2, a clinically relevant serine beta-lactamase, with the aim to tackle antimicrobial resistance (AMR) and restore beta-lactams antibiotic activity.

Boronic acids transition state inhibitors (BATSIs) have been extensively employed to inhibit beta-lactamases, a class of bacterial enzymes responsible for the most widespread mechanism of AMR against beta-lactam antibiotics.

However, the structural variety characterizing the different types of beta-lactamases imposes the development of novel beta-lactamases inhibitors (BLIs).

To fully exploit the potential of BATSIs as antibacterial agents and expedite the drug development process, KTGS will be used as a platform for drug discovery.

KTGS is an innovative strategy where the biological target is employed to catalyze the synthesis of its own best effective inhibitors from a library of reagents.

Triazole-based BATSIs, which have been reported to be potent and selective inhibitors of KPC-2, will be generated in a rapid and efficient way through KTGS (in situ click chemistry).

Given the strong interaction between BATSIs and their targets, KPC-2 will be employed as scaffold for the formation of potent and selective 1,4-disubstitued triazole-based BATSIs, starting from azido boronic acid warheads and functionalized alkynes.

In summary, this proposal seeks the development of novel BLIs drug candidates through the accomplishment of three objectives: 1) Investigation of KPC-2 as scaffold for in situ click chemistry and evaluation of the ability to generate triazole-based BATSI; 2) Discovery of novel inhibitors for KPC-2 using KTGS; 3) Identification of at least one highly active BATSI against clinically relevant beta-lactamases to be tested in vivo.

To accomplish these specific objectives, the project will be divided in three main work packages, which will involve a combination of biological, chemical, and analytical skills