Understanding the role of KTGS as platform for discovery of novel β-lactamase inhibitors
Multidrug-resistant bacteria (MDR bacteria) are strains of bacteria that have acquired resistance to multiple classes of antibiotics, making them challenging to treat effectively. These bacteria have developed mechanisms to counteract the effects of various antibiotics, rendering them less susceptible or completely resistant to many commonly used drugs, including β-lactams. Some examples of MDR bacteria include carbapenem-resistant Enterobacteriaceae (CRE), and extensively drug-resistant tuberculosis (XDR-TB).
MDR bacteria pose significant challenges in healthcare settings. They can cause infections that are difficult to treat and may result in increased morbidity, mortality, and healthcare costs. Infections caused by MDR bacteria often require the use of broad-spectrum antibiotics, which can lead to further antibiotic resistance and complications. Thus, they are a significant component of the global problem of antimicrobial resistance (AMR).
Among different mechanism of bacterial resistance, β-lactamases, a family of bacterial enzymes, are accountable for the most widespread mechanism of AMR. To overcome this challenge, the development of novel β-lactamases inhibitors (BLIs) is urgently needed.
The EU-funded BLISS seeks to explore the potential of Kinetic Target-Guided Synthesis (KTGS) as a pioneering platform to generate new BLIs with high selectivity and potency.
KTGS is a unique strategy for drug discovery where a biological macromolecule is employed to catalyse the synthesis of its own inhibitors from a library of reagents. In KTGS, “warhead-bearing reagents” are often used to drive the reaction within the biological target, i.e. enzymes, therefore allowing the target active site to discriminate among a selection of ligands with the best electronic and/or steric properties.
Hence, if successful, this strategy can shorten dramatically time and costs related to the development of potent BLIs. Combining a multidisciplinary approach and the expertise of Dr Nicolò Santi, Prof. Emilia Caselli and Prof. Fabio Prati, BLISS aims to evolve drug discovery to a higher level.