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

Olorofim是新的Orotomide类抗真菌药物的第一个成员[1]，对最常见的人类霉菌病原体烟曲霉(Af)[2]具有杀菌作用，在免疫抑制的侵袭性真菌模型中非常有效[3]。Cidality很重要，因为抗真菌疗法通常具有高死亡率(50%-80%)。目前只有3种不同的抗真菌药物用于治疗严重的系统性感染。占主导地位的药物类--氮唑类药物的死亡率仍然很高，在北欧，耐药性尤其高。两性霉素是剧毒的。棘球菌素只对Af有抑菌作用。迫切需要新的作用机制的药物。Olorofim抑制二氢罗丹酸脱氢酶(DHODH)，DHODH是嘧啶合成中一种必不可少的酶，强烈选择人类Af同工酶(2000：1)。在模型萌芽酵母中，对于任何被测试的代谢物(例如磷酸盐，t.5，25天)，嘧啶饥饿比饥饿更快地致死(t.5，16小时)，因为没有嘧啶饥饿计划[4]。对Olorofim的更深入的基础了解将有助于进一步开发针对其他病原体中相同酶的Orotomide，以及开发具有相关靶点的新抗菌药。细胞死亡的方式仍不清楚。嘧啶类化合物不仅是核酸的基石，也是磷脂和真菌细胞壁葡聚糖的基石。后者是Olorofim最明显的杀灭目标，因为它导致菌丝溶解[2]。棘球菌素也以细胞壁为靶标，它没有杀伤力，这表明Olorofim靶向的额外的非细胞壁途径是其成功的基础。

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.