Pathways to New Anti-infective Agents

我们迫切需要新的抗生素。目前用于治疗感染性疾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。随着病原体对这些分子产生耐药性，现有的抗生素已经变得不那么有效。因此，我们需要发现新的抗生素，并开发方法来多样化/优化这些分子的结构，如果我们要对抗新出现的抗菌素耐药性（AMR）。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，来创造新的酶和途径，提供新型抗生素。我们将集中在杂合非核糖体肽和聚酮化合物的天然产物，显示出有前途的抗菌活性。最初，我们将表征这些天然产物生物合成所需的关键酶，包括非核糖体肽合成酶（NRPS）和聚酮合酶（PKS）装配线酶，以及引入对活性至关重要的功能的定制酶。然后，我们将使用这些知识来指导NRPS/PKS酶的工程化，这些酶接受替代底物并进化出新的剪裁酶以衍生化并进一步使抗生素支架多样化。此外，鉴于最近的大流行，已经鉴定了几种新的抗病毒靶向化合物，其具有抑制SARS-Cov-2复制的潜力。这些抗病毒分子的酶途径也将被探索。

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.