Developing a new class of anti-fungals to face the threat of multidrug resistant Candida auris

开发新型抗真菌药物以应对多重耐药耳念珠菌的威胁

• 批准号: 2549674
• 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: 2021
• 资助国家: 英国
• 起止时间: 2021 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=studentship-2549674
• 关键词: Developing; new; class; anti; fungals

Invasive fungal infections kill 1,500,000/year globally (>4,000/y in the UK). The numbers are rising as more patients both in ITU and the community are long-term immunosuppressed with portals of entry, such as PICC lines. The evolutionary proximity of fungi and humans makes it hard to design therapeutic targets. Currently, there are three main antifungal classes: azoles, amphotericin (both targeting fungal sterols) and echinocandins (targeting the cell wall). Many fungi are resistant to first line therapy, azoles, particularly in Northern Europe. Amphotericin is highly toxic. Echinocandins are only fungistatic so cure is slow, and is vulnerable to resistance arising [1]. Agents with novel mechanisms of action are urgently required.In 2009 the first case was reported in Japan of a new invasive fungus: Candida auris. It is resistant to azoles and amphotericin, and rapidly develops resistance to echinocandins. C auris outbreaks have since occurred in all continents, causing wound infections and septicaemia mainly in ITUs,. The first European outbreak spanned 18 months at the Royal Brompton Hospital: 63 patients were colonised superficially, 9 others had invasive fungoses (no deaths attributed). Other European hospitals fared worse [2]. Nosocomial infection is a risk because C auris persists in the environment and is resistant to common cleaning regimens. Olorofim is the founder member of the Orotomides, a new antifungal class [3]. It kills the most common human mould pathogen Aspergillus fumigatus [4], and is highly effective in immuno-suppressed invasive models [5]. It is well-tolerated ,and the late stages of an international multi-centre Phase 2b trial are promising. In mid-2020 F2G received $61M financing to fund late stage development.Olorofim targets the enzyme dihydroorotic acid dehydrogenase (DHODH), which carries out an essential step in pyrimidine synthesis. Olorofim strongly selects (2000:1) for the A fumigatus enzyme cf both Candida and human orthologues. DHODH is cidal because cells have no pyrimidine rescue programme.AimsWe will design and test a new orotomide to target C auris DHODHObjectives1. Validate C auris DHODH as a target2. Determine which orotomide groups need optimisation to bind C auris DHODH3. Design orotomides modified to optimise interactions with C auris DHODH4. Test efficacy of new compounds: in vitro and in vivo models

侵袭性真菌感染在全球每年杀死1，500，000人（在英国> 4，000人/年）。随着国际电联和社区中越来越多的患者长期受到免疫抑制，如PICC线。真菌和人类在进化上的相似性使得设计治疗靶点变得困难。目前，有三种主要的抗真菌剂类别：唑类、阿替霉素（均针对真菌固醇）和棘白菌素（针对细胞壁）。许多真菌对一线治疗药物唑类具有耐药性，特别是在北方欧洲。两性霉素毒性很强。棘白菌素仅具有抑制真菌的作用，因此治疗缓慢，并且容易产生耐药性[1]。2009年，日本报道了第一例新的侵袭性真菌：耳念珠菌。它对唑类和阿替霉素具有耐药性，并迅速对棘白菌素产生耐药性。此后，各大洲都发生了耳道线虫疫情，造成伤口感染和败血症，主要发生在国际电联。第一次欧洲爆发在皇家布朗普顿医院持续了18个月：63名患者在表面定植，9人患有侵袭性真菌病（没有死亡归因）。其他欧洲医院的情况更糟[2]。医院感染是一种风险，因为耳念珠菌持续存在于环境中，并且对常见的清洁方案有抵抗力。Olorofim是Orotomides的创始成员，Orotomides是一种新的抗真菌类别[3]。它可以杀死最常见的人类霉菌病原体烟曲霉[4]，并且在免疫抑制的侵袭性模型中非常有效[5]。它的耐受性良好，国际多中心2b期试验的后期阶段是有希望的。2020年年中，F2 G获得了6100万美元的融资，用于后期开发。Olorofim的目标是二氢乳清酸脱氢酶（DHODH），该酶是嘧啶合成的重要步骤。Olorofim强烈选择（2000：1）烟曲霉酶，包括念珠菌和人类直系同源物。DHODH是杀细胞的，因为细胞没有嘧啶拯救程序。以人耳DHODH为靶点2.确定哪些orotomide基团需要优化，以结合耳念珠菌DHODH 3。修改设计orotomides以优化与耳念珠菌DHODH 4的相互作用。测试新化合物的功效：体外和体内模型