Sulfur Assimilation Pathway: New Antifungal Targets

描述（由申请人提供）：真菌感染，最常见的由白色念珠菌引起，目前是医院获得性血液感染的第四大原因，与最高的归因于死亡率相关。已经提出了许多策略来确定治疗全身白色念珠菌感染的新代谢靶点。然而，这些计划中绝大多数都缺少对真菌体内代谢的理解。硫同化途径是抗真菌药物开发的一个有希望的重点。在提出的研究中，我们将使用遗传方法来定义生物如何在播散性感染的动物模型中吸收硫。我们建议研究导致硫酸盐还原为硫化物的途径的重要性，硫化物与碳受体的结合，以及后者对半胱氨酸和蛋氨酸合成的引导。我们还将确定这些过程是否随宿主感染生态位的功能而变化。根据念珠菌基因组的注释，很明显，真菌（以及大多数传染性生物）中的硫通量在几个重要的点上与人类不同。因此，拟议的工作将确定这些差异是否值得作为新疗法的靶点。公共卫生相关性：真菌感染越来越重要，通常是侵入性医疗程序的致命并发症，从新生儿的持续治疗到骨髓移植、化疗和深部外科手术。拟议的研究将确定白色念珠菌，与医院感染相关的最常见的真菌病原体，如何吸收和利用必需的营养物质硫。初步的研究强化了这样的假设，即硫同化途径，包括没有哺乳动物对应的独特酶，如果更好地理解，可以为开发新的抗真菌疗法定义新的靶点。

DESCRIPTION (provided by applicant): Fungal infections, most commonly caused by Candida albicans, are currently the fourth leading cause of hospital-acquired bloodstream infections and are associated with the highest rate of attributed mortality. Numerous strategies have been forwarded to define new metabolic targets for the treatment of systemic C. albicans infections. Critically missing from the vast majority of these plans, however, is an understanding of fungal metabolism in vivo. One promising focus for anti-fungal drug development is the sulfur assimilation pathway. In the proposed study we will use a genetic approach to define how the organism assimilates sulfur in an animal model of disseminated infection. We propose to investigate the importance of pathways that lead to the reduction of sulfate to sulfide, the incorporation of sulfide into carbon acceptors, and the channeling of the latter towards the synthesis of cysteine and methionine. We will also determine whether these processes vary as a function of infection niche within the host. Based on the annotation of the Candida genome, it is clear that sulfur fluxes in the fungus (and for that matter in most infectious organisms) differ at several important points from those in humans. The proposed work will thus determine whether these differences merit attention as targets for novel therapies. PUBLIC HEALTH RELEVANCE: Fungal infections are increasingly important, often fatal complications of intrusive medical procedures ranging from the sustaining therapies for neonates to bone marrow transplantation, chemotherapy and deep surgical procedures. The proposed study will determine how Candida albicans, the most common fungal pathogen associated with hospital infections, assimilates and uses the essential nutrient-sulfur. Preliminary studies reinforce the hypothesis that the sulfur assimilation pathways, which include unique enzymes without mammalian counterpart, could, if better understood, define new targets for the development of new anti-fungal therapies.