Targetting Penicillin Binding Proteins with dual targetting non-beta lactam antibiotics and Fragment based drug discovery

The development and response to Antimicrobial Resistance (AMR) is now widely understood to be a global healthcare emergency. It is widely acknowledged in academia and industry that next generation antibiotic drugs are mostly likely to come from new approaches to inhibiting existing, validated antibiotic drug targets. Outside the bacterial cytoplasmic membrane, there is a sugar-based polymer called peptidoglycan (PG) crosslinked by peptide bridges, which gives the cell wall strength, rigidity, cell shape characteristics and is a scaffold for a multitude of other molecular structures. The formation of PG is performed by a group of enzymes called penicillin binding proteins (PBPs) which are responsible for formation of the sugar backbone and its crosslinking by peptide bridges and are thus well established targets for antibiotics. Disruptions of the PG structure itself or inhibition of the synthesising enzymes by antibiotics, results in cell lysis or cessation of cell growth. Generations of penicillin-based antibiotics have been used clinically to interfere with the crosslinking activity of these enzymes and have been backbone of antimicrobial therapy for many decades. However, resistance to these drugs has occurred by a variety of mechanisms including the recruitment and production of enzymes, which degrade the penicillin chemical structure before it can reach its target. Our project will seek to study and evaluate these enzymes with a series of non-penicillin based compounds, which show promise for next generation antibiotics. In addition, we will use state of the art methods to evaluate the potential of using chemical fragments to build novel inhibitor species to these important cell wall biosynthetic proteins. This project will advance our knowledge of these proteins and contribute to the evaluation and development of next generation antibiotics.