How transcriptional regulation governs fungal drug resistance

抗生素耐药性（AMR）是一个严重的临床和社会问题，当使用药物治疗人类和其他动物的感染。耐药性的一个常见原因是“外排泵”的过度产生，它通过将药物泵出细胞而大大降低了药物的有效性。鉴于药物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抑制药物外排泵的过度产生是至关重要的。在本项目中，我们将阐明如何控制致病真菌光滑念珠菌中药物外排泵的产生。C.光滑是真菌感染的最常见原因之一。C. glabrata感染与免疫力受损的个体的高死亡率相关，所述免疫力受损的个体包括用化疗治疗的癌症患者和服用免疫抑制药物的移植受者。C.光滑念珠菌感染人类和其它动物，例如，鸟和牛。C.作为真菌病原体，光滑念珠菌是特别致命的，因为它对唑类抗真菌剂的敏感性低，并且由于外排泵的过度产生而容易产生耐药性。防止这些外排泵的过度生产是确保C。glabrata可以被现有的抗真菌药物杀死。然而，泵的过度生产机制还没有得到充分的了解，我们来防止它。本项目的目的是揭示泵的过度生产机制，以防止耐药性。利用我们团队在感染性疾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物在调节泵基因表达中的功能。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。这项工作对了解念珠菌抗真菌耐药机制具有巨大的直接和长期潜力。glabrata的抗真菌作用，以及对抗C.光滑念珠菌和潜在的其它念珠菌属物种。

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.