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

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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