Antifungal drug target prioritization using Cryptococcus neoformans

描述(申请人提供)：真菌疾病在人类中非常常见。这些疾病包括轻微的美容症状、反复出现的皮肤和粘膜表面感染，以及较罕见的由播散性真菌引起的危及生命的疾病，特别是在免疫功能受损的患者中，如艾滋病患者、接受化疗或皮质类固醇治疗的患者和器官移植接受者。目前，可用于治疗真菌的药物种类有限。有些物种对这些药物具有天然抗药性，可以在临床环境中获得抗药性。因此，迫切需要开发治疗真菌疾病的新方法。这项建议的目的是利用模式生物新生隐球菌(担子菌门)，确定适合真菌药物开发的靶点。这种真菌与通常研究的致病或模式物种如白色念珠菌、酿酒酵母或裂殖酵母(子囊菌门)非常不同，因此在这种生物中的发现有望扩展到所有病原真菌。这项拟议的研究的具体目的是使用两种实验方法来识别新生葡萄球菌的必要基因。必需基因是生存所必需的：因为突变株不能生长，所以鉴定必需基因是一项技术挑战。在这里，这些基因将通过创新的基因筛查和生物信息学优先排序来识别，这些基因存在于真菌中，但不存在于人类中。该提议还将产生适合于利用单倍体不足进行小分子研究的杂合子菌株资源。这些必需基因的发现代表了抗真菌药物开发的新途径。 公共卫生相关性：这项研究的意义和对人类健康的好处是提供了对所有真菌保守的基本基因的全面了解，以及对真菌与其近亲动物界区别开的分子基础的洞察。鉴定真菌必需基因的长期目标是将其用于合理的药物设计，从而为人类感染性疾病的治疗提供新的治疗途径。

DESCRIPTION (provided by applicant): Fungal diseases in humans are extremely common. They include mild cosmetic symptoms, recurrent skin and mucosal surface infections, and the rarer life-threatening diseases caused by disseminated fungi particularly in immunocompromised patients such as those suffering from AIDS, undergoing chemotherapy or corticosteroid therapy, and organ transplant recipients. Currently there is a limited repertoire of drugs available to treat fungi. Some species are naturally resistance to these drugs and resistance can be acquired in clinical settings. Thus, there is an urgent need to develop new treatments for fungal diseases. The objective of this proposal is to identify suitable targets for drug development in fungi, using a model organism Cryptococcus neoformans (in phylum Basidiomycota). This fungus is very diverged and different from commonly studied pathogenic or model species like Candida albicans, Saccharomyces cerevisiae or Schizosaccharomyces pombe (in phylum Ascomycota), and thus discoveries made in this organism are expected to extend across all pathogenic fungi. The specific aim of the proposed research is to identify essential genes of C. neoformans, using two experimental approaches. Essential genes are those required for viability: because mutants cannot grow, the identification of essential genes is a technical challenge. Here these genes will be identified by an innovative genetic screen and through a bioinformatic prioritization to essential genes found in fungi but not in humans. The proposal will also generate a resource of heterozygous strains suitable for small molecule studies utilizing haplo-insufficiency. The discovery of these essential genes represents new avenues for the development of antifungal agents. PUBLIC HEALTH RELEVANCE: The significance of this research and the benefit to human health is providing a comprehensive understanding of conserved essential genes for all fungi, with insights into the molecular basis that distinguishes fungi from their closest relatives, the animal kingdom. The long-term objective of identifying essential fungal genes is in their use in rational drug design, thus providing new therapeutic avenues for the treatment of human infectious diseases.