BLISS · Beta-Lactamase Inhibitors Synthesised through in Situ click chemistry

Beta-Lactamase Inhibitors Synthesised through in Situ click chemistry

The BLISS (Beta-Lactamase Inhibitors Synthesised through in Situ click chemistry) project aims to directly address the critical global challenge of antimicrobial resistance (AMR), specifically targeting β-lactamases, enzymes responsible for deactivating β-lactam antibiotics. AMR is a growing threat to public health, as β-lactam antibiotics are among the most widely used and effective treatments for bacterial infections. The production of β-lactamases, particularly serine β-lactamases (SBLs), is the primary mechanism behind the resistance of Gram-negative bacteria to these antibiotics. The development of novel β-lactamase inhibitors (BLIs) is essential to overcoming this resistance and restoring the efficacy of β-lactam antibiotics. BLISS focuses on the use of Kinetic Target-Guided Synthesis (KTGS), a breakthrough approach, to allow for the rapid and cost-effective discovery of potent and selective boronic acid transition-state inhibitors (BATSIs). In this project, β-lactamases are used as a template to drive the identification of inhibitors directly from a library of reagents, potentially reducing the time and resources typically required in traditional drug discovery methods. This approach enables the generation of BATSIs specifically targeting a range of β-lactamases involved in AMR, with promising efficiency. This multidisciplinary project aims to achieve key milestones in the discovery of novel BATSIs. Using KTGS, several boronic acid-based inhibitors were identified and demonstrated strong activity against different β-lactamase variants, including KPC-2, a critical enzyme in resistant bacterial strains. These inhibitors exhibited the potential to restore the activity of β-lactam antibiotics, highlighting their promise for further development in AMR treatment strategies. Importantly, the KTGS platform also allowed for the identification of BATSIs with minimal resource use, enhancing the overall cost-effectiveness of the drug development process. The primary objectives of BLISS are: 1. Investigate the use of KTGS to generate potent BATSIs targeting β-lactamases involved in AMR; 2. Discover novel and effective BLIs capable of restoring the efficacy of β-lactam antibiotics; The outcomes of BLISS hold the potential to aid future AMR treatment strategies, contributing to an efficient alternative method for discovering novel BLIs and ensuring the continued effectiveness of β-lactam antibiotics. In addition to its scientific impact, BLISS contributes to the European Union strategic goals by addressing the pressing need for novel antimicrobial agents and offering a cost-effective approach to drug discovery, potentially reducing healthcare costs associated with AMR. This work also aligns with broader societal and economic objectives by combating a global health threat and fostering innovation in pharmaceutical development.

Текст от CORDIS, на английски · Данни: CORDIS, © Европейски съюз