Decphering the network of genes involved in the emergence of drug resistance in the human fungal pathogen Candida glabrata

威胁生命的感染是一个日益严重的现实。几乎所有医院都存在耐多药细菌，如耐甲氧西林金黄色葡萄球菌，社区获得性结核病往往不愿接受治疗。不太为人所知的是假丝酵母菌属的真菌，但在英国造成的死亡人数是MRSA的四到五倍。它们通常与“鹅口疮”等黏膜感染有关，但每年在全球范围内造成40万例危及生命的感染，特别是在免疫抑制的患者群体中。主要病原菌之一为光滑假丝酵母菌。这种真菌以单细胞单倍体酵母的形式生长，对宿主的天然防御具有高度的抵抗力，并对许多临床使用的抗真菌药物，包括一线的氮唑和棘球菌素产生抗药性。即使有最好的医疗护理，感染这种酵母菌也会导致约50%的死亡，光滑念珠菌感染的发生率正在稳步攀升。这要求开发新的抗真菌疗法，以针对耐药真菌感染，如光滑念珠菌。为了解决这个问题，该项目利用对常见抗真菌耐药机制的遗传洞察来确定可以有针对性地防止耐药的阿喀琉斯脚跟。这种方法可以为开发耐药感染的治疗方法提供一个强有力的工具。

Life threatening infections are an increasing reality. Multi-drug resistant bacteria such as MRSA are present in nearly all hospitals, and community acquired TB is often recalcitrant to treatment. Less well known, but causing four to five times more deaths in the UK than MRSA, are fungi in the genus Candida. These are commonly associated with mucosal infections such as "thrush", but are responsible for > 400,000 life-threatening infections worldwide every year, especially in the immunosuppressed patient population. One of the principle pathogens is Candida glabrata. This fungus grows as a single celled haploid yeast, and is highly resistant to host innate defences and can acquire resistance to many clinically used antifungal drugs, including the frontline azoles and echinocandins. Even with the best possible medical care, infections with this yeast cause ~50% mortality and the incidence of C. glabrata infections is steadily climbing. This demands that novel antifungal therapies are developed that can target drug resistant fungal infections such as C. glabrata. To address this, this project leverages genetic insights into common antifungal resistance mechanisms to identify an achilles heel that can be targeted to prevent resistance. Such an approach could provide a powerful tool in developing treatments for drug resistant infections.