Engineering microbial cell factories for production of improved polyene antifungal agents

工程微生物细胞工厂用于生产改进的多烯抗真菌剂

• 批准号: 2898887
• 金额: --
• 依托单位: University of Manchester
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2023
• 资助国家: 英国
• 起止时间: 2023 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2898887
• 关键词: Engineering; microbial; cell; factories; production

Fungal infections are an escalating global threat to human health. The fewantifungal agents currently available are becoming increasingly ineffective due to emergingmultidrug resistant pathogens (e.g. Aspergillus fumigatus, Candida albicans & Candida auris).Despite the acute need for alternative treatments, very few new drug candidates have emerged inrecent years, and we remain reliant on a few established antifungals, particularly polyenesincluding WHO essential medicines amphotericin B (AmB), nystatin (Nys) and pimaricin (Pim).Polyenes are complex cyclic polyketide macrolides produced by Actinobacteria. Given polyeneshave potent broad-spectrum activity and the incidence of resistance to them is relatively low, theyremain the most effective and widely used antifungal agents. AmB, which is produced byStreptomyces nodosus, is the frontline treatment for many common systemic fungal infections.Recently, AmB was used to combat the outbreak of COVID-19 associated mucormycosis (blackfungus). AmB is also an essential treatment of the parasitic disease leishmaniasis which causeshigh mortality in the developing world. Despite their medical importance, polyenes exhibitsevere toxicity, and there is an urgent need for safer, less toxic alternatives. SAR shows that anexocyclic C16-carboxylate in AmB, which is also present in the majority of the otherpolyenes, is a key determinant of toxicity. AmB derivatives lacking this moiety are significantly lesstoxic and chemical modification of the C16-carboxylate also affords derivatives with loweredtoxicity.In addition to C16-modification, conjugation of polyenes with sugars and other moieties that improve solubility and reduce aggregation can also reduce toxicity. However,chemical synthesis of complex polyenes is very challenging, requiring multiple steps, deleteriousreagents and extensive use of protecting groups, which is expensive, unsustainable and difficult toscale-up. In this project we aim to engineer microbial cell factories, that can deliver safer polyenevariants with improved activity and lower toxicity via a sustainable single-step fermentationapproach.

真菌感染对人类健康构成日益严重的全球威胁。由于新出现的多重耐药病原体（例如烟曲霉、白色念珠菌和耳念珠菌），目前可用的少数抗真菌药物变得越来越无效。尽管迫切需要替代治疗，但近年来出现的新候选药物很少，我们仍然依赖一些现有的抗真菌药物，特别是多烯类药物，包括世卫组织基本药物 两性霉素 B (AmB)、制霉菌素 (Nys) 和匹马霉素 (Pim)。多烯是由放线菌产生的复杂环状聚酮大环内酯。鉴于多烯具有有效的广谱活性，且耐药性发生率相对较低，因此它们仍然是最有效和最广泛使用的抗真菌剂。 AmB 由结节链霉菌产生，是许多常见全身性真菌感染的一线治疗药物。最近，AmB 被用于对抗 COVID-19 相关毛霉菌病（黑真菌）的爆发。 AmB 也是治疗导致发展中国家高死亡率的寄生虫病利什曼病的重要方法。尽管多烯具有重要的医学意义，但它们表现出严重的毒性，因此迫切需要更安全、毒性更低的替代品。 SAR 表明 AmB 中的外环 C16-羧酸盐（也存在于大多数其他多烯中）是毒性的关键决定因素。缺乏该部分的AmB衍生物的毒性显着降低，并且C16-羧酸酯的化学修饰也提供了毒性降低的衍生物。除了C16-修饰之外，多烯与糖和其他提高溶解度和减少聚集的部分的缀合也可以降低毒性。然而，复杂多烯的化学合成非常具有挑战性，需要多个步骤、有害试剂和大量使用保护基团，成本昂贵、不可持续且难以扩大规模。在这个项目中，我们的目标是设计微生物细胞工厂，通过可持续的单步发酵方法提供更安全的多烯变体，提高活性并降低毒性。