Antifungal drug target prioritization using Cryptococcus neoformans

描述（由申请人提供）：人类真菌性疾病极为常见。它们包括轻微的美容症状，复发性皮肤和粘膜表面感染，以及由播散性真菌引起的更罕见的危及生命的疾病，特别是在免疫功能低下的患者中，例如患有艾滋病、接受化疗或皮质类固醇治疗的患者以及器官移植接受者。目前，可用于治疗真菌的药物库有限。一些物种对这些药物具有天然耐药性，并且在临床环境中可以获得耐药性。因此，迫切需要开发新的真菌疾病治疗方法。本提案的目的是使用模式生物新型隐球菌（担子菌门）确定真菌中药物开发的合适靶点。这种真菌是非常分歧的，不同于通常研究的致病性或模式物种，如白色念珠菌，酿酒酵母或粟酒裂殖酵母（子囊菌门），因此在这种生物体中的发现预计将扩展到所有致病性真菌。本研究的具体目的是鉴定C. neoformans，using使用two experimental实验approaches方法.必需基因是生存所必需的基因：由于突变体不能生长，必需基因的鉴定是一项技术挑战。在这里，这些基因将通过创新的遗传筛选和生物信息学优先级来确定在真菌中发现的而不是在人类中发现的必需基因。该提案还将产生一个杂合菌株的资源，适用于利用单倍不足的小分子研究。这些必需基因的发现为抗真菌药物的开发提供了新的途径。 公共卫生相关性：这项研究的意义和对人类健康的益处在于全面了解所有真菌的保守必需基因，深入了解真菌与其近亲动物界的分子基础。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，从而为治疗人类感染性疾病提供新的治疗途径。

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.