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.

真菌感染是对人类健康的全球威胁。 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两性霉素B（AMB），Nystatin（NYS）和皮马列蛋白（PIM）。聚丙烯是肌动杆菌产生的复杂循环聚酮化合物。考虑到多恒射效果的宽光谱活性和对其抗性的发生率相对较低，它们是最有效，最广泛使用的抗真菌剂的。 AMB是肌链霉菌肿瘤的产生的，是许多常见的全身真菌感染的一线处理。 AMB也是对寄生虫疾病利什曼病的重要治疗方法，该疾病在发展中国家的死亡率。尽管具有医学意义，但Polyenes展示了毒性的毒性，并且迫切需要更安全，毒性较小的替代品。 SAR表明，在大多数其他聚集烯中也存在的AMB中的Anexocyclic C16-羧酸盐是毒性的关键决定因素。缺乏这种部分的AMB衍生物显着较小，C16-羧酸盐的化学修饰也提供了降低毒性的衍生物。除了C16模型，多烯与糖和其他基因座的结合，可改善溶质和降低聚集的糖节，还可以降低毒性。但是，复杂多烯的化学合成非常具有挑战性，需要多个步骤，有效的酸味和广泛使用保护组，这是昂贵，不可持续且困难的toscale-up。在这个项目中，我们旨在设计微生物细胞工厂，该工厂可以通过可持续的单步发酵方法提供具有改善活性和降低毒性的更安全的多元素。