Pathways to New Anti-infective Agents

迫切需要新的抗生素。今天用于治疗传染病的大多数抗生素是由微生物产生的小分子，称为天然产物或其衍生物。现有的抗生素已经变得不那么有效，因为病原体对这些分子产生了抗药性。因此，如果我们要对抗新出现的抗菌素耐药性(AMR)，我们需要发现新的抗生素，并开发方法使这些分子结构多样化/优化。在这个项目中，我们的目标是使用最先进的合成生物学技术，包括CRISPR-Cas9基因编辑和定向进化，来创造新的酶和提供新型抗生素的途径。我们将专注于杂交的非核糖体肽和聚酮类天然产物，它们具有良好的抗菌活性。首先，我们将描述这些天然产品生物合成所需的关键酶的特征，包括非核糖体肽合成酶(NRPS)和聚酮合成酶(PKS)装配线酶，以及引入对活动至关重要的功能的剪裁酶。然后，我们将使用这些知识来指导NRPS/PKS酶的工程，这些酶可以接受替代底物，并进化出新的剪裁酶来衍生和进一步多样化抗生素支架。此外，鉴于最近的大流行，已经确定了几种新的抗病毒靶标化合物，它们有可能抑制SARS-CoV-2的复制。还将探索这些抗病毒分子的酶途径。

There is an urgent need for new antibiotics. The majority of antibiotics that are used to treat infectious diseases today are small molecules produced by microorganisms, called natural products, or derivatives thereof. The existing antibiotics have become less effective as pathogens evolve resistance to these molecules. Consequently, we need to discover new antibiotics and also develop methods to diversify/optimise the structure of these molecules if we are to combat emerging antimicrobial resistance (AMR). In this project, we aim to use state-of-the-art synthetic biology technologies, including CRISPR-cas9 gene editing and directed evolution, to create new enzymes and pathways that deliver novel antibiotics. We will focus on hybrid nonribosomal peptide and polyketide natural products that show promising antimicrobial activity. Initially we will characterise the key enzymes required for the biosynthesis of these natural products, including non-ribosomal peptide synthetase (NRPS) and polyketide synthase (PKS) assembly line enzymes, as well as the tailoring enzymes that introduce functionality that is essential for activity. We will then use this knowledge to guide engineering of NRPS/PKS enzymes that accept alternative substrates and evolve new tailoring enzymes to derivatise and further diversify the antibiotic scaffolds. Also, in light of the recent pandemic, several novel anti-viral target compounds have been identified which have potential to inhibit replication of SARS-Cov-2. Enzymatic pathways to these anti-viral molecules will also be explored.