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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-l... ver más

15/10/2024

UNIMORE

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UNIVERSITA DEGLI STUDI DI MODENA E REGGIO EMI... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Fecha límite participación Sin fecha límite de participación.

Financiación concedida El organismo HORIZON EUROPE notifico la concesión del proyecto el día 2024-10-15

HORIZON-MSCA-2021-PF-01-01: MSCA Postdoctoral Fellowships 2021 ExpectedOutcome:

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Duración del proyecto: 23 meses Fecha Inicio: 2022-10-16
Fecha Fin: 2024-10-15

Líder del proyecto

UNIVERSITA DEGLI STUDI DI MODENA E REGGIO EMI... No se ha especificado una descripción o un objeto social para esta compañía.

TRL 4-5

Fecha límite de participación Sin fecha límite de participación.

Descripción del proyecto 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

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