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

全球每年有1500,000人死于侵袭性真菌感染(英国每年有4000人死于侵袭性真菌感染)。随着ITU和社区中越来越多的患者长期受到PICC等进入门户的免疫抑制，这一数字正在上升。真菌和人类在进化上的接近，使得设计治疗靶点变得困难。目前，抗真菌药物主要有三类：唑类、两性霉素类(均以真菌甾醇为靶标)和棘球菌素类(以细胞壁为靶标)。许多真菌对一线疗法--氮唑类药物产生抗药性，特别是在北欧。两性霉素是剧毒的。棘球菌素只对真菌有抑制作用，所以治愈速度很慢，容易产生耐药性[1]。迫切需要具有新作用机制的药物。2009年，日本首次报告了一种新的入侵真菌：金黄色假丝酵母。它对唑类和两性霉素具有抗药性，并对棘球菌素迅速产生抗药性。自那以后，各大洲都爆发了Auris疫情，造成伤口感染和败血症，主要发生在图斯。第一次欧洲疫情在皇家布朗普顿医院爆发，时间跨度为18个月：63名患者表面定居，9名患者患有侵袭性真菌病(没有死亡原因)。其他欧洲医院的情况更糟[2]。医院感染是一种风险，因为金黄色葡萄球菌持续存在于环境中，对常见的清洁方案具有抵抗力。奥洛菲姆是一种新的抗真菌药物奥罗托米德的创始成员[3]。它能杀死最常见的人类霉菌烟曲霉[4]，在免疫抑制的侵入性模型中非常有效[5]。它的耐受性很好，国际多中心2b期试验的后期阶段很有希望。2020年年中，F2G获得了6100万美元的融资，为后期开发提供资金。Olorofim的目标是二氢罗丹酸脱氢酶(DHODH)，它是合成嘧啶的关键步骤。Olorofim强烈选择(2000：1)用于烟曲霉菌酶cf念珠菌和人类直系物。DHODH是杀伤性的，因为细胞没有嘧啶拯救计划。目的我们将设计并测试一种针对C Auris DHODHObjectives1的新的orotomide。将C Auris DHODH验证为目标2。确定哪些奥托咪胺基团需要优化以结合C Auris DHODH3。设计经修改的orotomide以优化与C Auris DHODH4的相互作用。新化合物的体外和体内药效试验

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