How does a new antimicrobial kill the fungi that invade immunosuppressed patients?

新的抗菌剂如何杀死侵入免疫抑制患者的真菌？

• 批准号: 2398039
• 金额: --
• 依托单位: University College London
• 依托单位国家: 英国
• 项目类别: Studentship
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2398039
• 关键词: How; does; new; antimicrobial; kill

Olorofim, the first member of the new Orotomide class of antifungals [1], is fungicidal against the most common human mould pathogen Aspergillus fumigatus (Af) [2], and is highly effective in immunosuppressed invasive fungal models [3]. Cidality is important, as fungistatic therapies often carry high mortality (50-80%). There are currently only 3 distinct antifungal classes for serious systemic infections. Azoles, the dominant drug class, still have significant mortality, and resistance is particularly high in Northern Europe. Amphotericin is highly toxic. Echinocandins are only fungistatic to Af. New agents with novel mechanisms of action are urgently required.Olorofim inhibits dihydroorotic acid dehydrogenase (DHODH), an essential ubiquitous enzyme in pyrimidine synthesis, strongly selecting for Af isozyme cf human (2000:1). In model budding yeast, pyrimidine starvation is lethal more rapidly (t.5 16 hours) than starvation for any metabolite tested (e.g. phosphate t.5 25 days) because there is no pyrimidine starvation programme [4]. Greater fundamental understanding of Olorofim will support development both of further orotomides targeting the same enzyme in other pathogens and of new antimicrobials with related targets. The mode of cell death is still not clear. Pyrimidines are building blocks not only for nucleic acids, but also for phospholipids and fungal cell wall glucans. The latter is the most obvious target for cidality by Olorofim, as it causes Af hyphal lysis [2]. The lack of cidality by echinocandins, which also target the cell wall, suggests that additional, non-cell wall pathways targeted by Olorofim underlie its success.

Olorofim是新的Orotomide类抗真菌药的第一个成员[1]，对最常见的人类霉菌病原体烟曲霉（Af）具有杀真菌作用[2]，并且在免疫抑制的侵袭性真菌模型中非常有效[3]。毒性很重要，因为真菌抑制疗法通常具有高死亡率（50-80%）。目前只有3个不同的抗真菌类严重全身感染。唑类是主要的药物类别，仍然具有显著的死亡率，并且在北方欧洲的耐药性特别高。两性霉素毒性很强。棘白菌素仅对Af具有抑菌作用，因此迫切需要具有新作用机制的新药物。Olorofim抑制二氢乳清酸脱氢酶（DHODH），DHODH是嘧啶合成中普遍存在的重要酶，对人类Af同工酶具有强烈选择性（2000：1）。在模型芽殖酵母中，嘧啶饥饿比任何测试代谢物的饥饿（例如磷酸盐t.5 25天）更快地致死（t.5 16小时），因为没有嘧啶饥饿程序[4]。对Olorofim的更深入的基本了解将支持开发针对其他病原体中相同酶的进一步的orotomides以及具有相关靶点的新型抗菌药物。细胞死亡的方式尚不清楚。嘧啶不仅是核酸的结构单元，也是磷脂和真菌细胞壁葡聚糖的结构单元。后者是Olorofim致敏性的最明显目标，因为它导致Af菌丝溶解[2]。棘白菌素也针对细胞壁，但缺乏杀伤性，这表明Olorofim针对的其他非细胞壁途径是其成功的基础。