Sulfur Assimilation Pathway: New Antifungal Targets

描述(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，与最高的归因性死亡率有关。已经提出了许多战略，以确定治疗系统性白念珠菌感染的新的代谢目标。然而，这些计划中的绝大多数都缺少对真菌在体内新陈代谢的了解。硫磺同化途径是抗真菌药物开发的一个有前景的焦点。在这项拟议的研究中，我们将使用遗传方法来定义在播散性感染的动物模型中有机体如何吸收硫。我们建议研究导致硫酸盐还原为硫化物、将硫化物结合到碳受体中以及后者通向半胱氨酸和蛋氨酸合成的途径的重要性。我们还将确定这些过程是否会随着宿主内感染生态位的变化而变化。根据对念珠菌基因组的注释，很明显，真菌中的硫通量(就这一点而言，在大多数感染性生物中)在几个重要的点上与人类的不同。因此，拟议的工作将确定这些差异是否值得关注，作为新疗法的目标。与公共卫生相关：真菌感染日益重要，往往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、化疗和深度外科手术。这项拟议的研究将确定白色念珠菌--与医院感染有关的最常见的真菌病原体--如何吸收和利用必要的营养-硫磺。初步研究证实了这样的假设，即硫同化途径，包括没有哺乳动物对应的独特酶，如果更好地了解，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.