How transcriptional regulation governs fungal drug resistance

在使用药物治疗人类和其他动物的感染时，抗菌素耐药性(AMR)是一个严重的临床和社会问题。耐药的一个常见原因是“外排泵”的过度生产，这种泵通过将药物泵出细胞而极大地降低药物的有效性。鉴于外排泵水平对耐药性的重要性，了解细胞如何调节药物外排泵的产生以及如何阻止药物外排泵的过度生产是至关重要的。在这个项目中，我们将阐明致病真菌光滑假丝酵母中药物外排泵的产生是如何控制的。光滑假单胞菌是真菌感染最常见的原因之一。在免疫功能受损的人中，包括接受化疗的癌症患者和服用免疫抑制药物的移植受者，光滑毛滴虫感染与高死亡率有关。光滑毛囊线虫感染人类，也感染其他动物，如鸟类和牛。光滑假单胞菌是一种特别致命的真菌病原体，因为它对唑类抗真菌药物的敏感性较低，并且由于外排泵产量过高而容易产生抗药性。防止这些外排泵的过量生产是确保光滑隐孢子虫能够被现有抗真菌药物杀死的一个好方法。然而，对于泵的过度生产机制的认识还不够深入，我们不能很好地预防它。本项目的目的是揭示泵的过度生产机制，以防止耐药。利用我们团队在传染病和基因表达方面的专业知识，我们将剖析染色质重塑复合体在调节Pump基因表达方面的功能。我们还将探索通过使用遗传和蛋白质组学方法以及开发用于泵移除的创新生物技术来阻止耐药性的途径。这项工作对了解光滑念珠菌的抗真菌耐药性机制，以及对抗光滑念珠菌和潜在的其他念珠菌的抗真菌耐药性具有巨大的即时和长期潜力。

Antimicrobial resistance (AMR) is a serious clinical and societal problem when using drugs to treat infections in humans and other animals. A common cause of drug resistance is overproduction of 'efflux pumps', which greatly reduce the effectiveness of drugs by pumping them out of cells. Given the importance of efflux pump levels for drug resistance, it is vital to understand how cells regulate production of drug efflux pumps and how overproduction of the pumps can be prohibited.In this project, we will elucidate how the production of drug efflux pumps is controlled in the pathogenic fungus Candida glabrata. C. glabrata is one of the most common causes of fungal infections. C. glabrata infection is associated with high mortality in individuals with compromised immunity, including cancer patients treated with chemotherapy, and transplant recipients who take immunosuppressive drugs. C. glabrata infects humans and also other animals, e.g., birds and cattle. C. glabrata is particularly deadly as a fungal pathogen because it has low susceptibility to azole antifungal agents, and easily develops drug resistance due to overproduction of efflux pumps. Preventing overproduction of these efflux pumps is one good approach to ensure C. glabrata can be killed by existing antifungal drugs. However, overproduction mechanism of the pumps is not understood sufficiently well for us to prevent it.The aim of this project is to reveal mechanisms of overproduction of pumps in order to prevent drug resistance. Utilising our team's expertise in infectious diseases and gene expression, we will dissect the function of a chromatin remodeller complex in regulating pump gene expression. We will also explore pathways to stop drug resistance through using genetic and proteomic approaches and developing an innovative biotechnology for pump removal. This work holds enormous immediate and long-term potential for understanding mechanisms of antifungal resistance of C. glabrata, and for combating antifungal resistance of C. glabrata and potentially other Candida species.