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

抗生素耐药性（AMR）的发展和应对现在被广泛认为是一个全球性的医疗保健紧急情况。学术界和工业界普遍认为，下一代抗生素药物很可能来自抑制现有有效抗生素药物靶标的新方法。在细菌细胞质膜外，有一种被称为肽聚糖（PG）的糖基聚合物通过肽桥交联，它赋予细胞壁强度，刚度，细胞形状特征，并且是许多其他分子结构的支架。PG的形成是由一组称为青霉素结合蛋白（PBP）的酶完成的，这些酶负责糖骨架的形成及其通过肽桥的交联，因此是抗生素的公认靶标。PG结构本身的破坏或抗生素对合成酶的抑制导致细胞溶解或细胞生长停止。几代青霉素类抗生素已在临床上用于干扰这些酶的交联活性，几十年来一直是抗菌治疗的支柱。然而，对这些药物的耐药性是通过多种机制发生的，包括酶的募集和产生，这些酶在青霉素到达靶标之前降解青霉素的化学结构。我们的项目将寻求研究和评估这些酶与一系列非青霉素为基础的化合物，这表明下一代抗生素的前景。此外，我们将使用最先进的方法来评估使用化学片段来构建这些重要细胞壁生物合成蛋白的新型抑制剂种类的潜力。该项目将推进我们对这些蛋白质的了解，并有助于下一代抗生素的评估和开发。

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.