Sulfur Assimilation Pathway: New Antifungal Targets

硫同化途径：新的抗真菌靶点

• 批准号: 7849977
• 负责人: GEORGE Robert NEWPORT
• 金额: $ 19.26万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7849977
• 关键词: Ablation; Adenosine; Anabolism; Animal Model; Antifungal Agents; Antifungal Therapy; Assimilations; Attention; Attenuated; Bone Marrow Transplantation; Brucella melitensis; Candida; Candida albicans; Candidate Disease Gene; Carbon; Cells; Cryptococcus neoformans; Cysteine; Data; Development; Disseminated candidiasis; Elements; Enteral; Environment; Enzymes; Evaluation; Event; Gene Targeting; Genes; Genetic; Genome; Genomics; Growth; Homologous Gene; Hospitals; Human; Infection; Infectious Agent; Inorganic Sulfates; Lead; Lesion; Literature; Medical; Metabolic; Metabolism; Methionine; Microbial Biofilms; Modeling; Mycobacterium tuberculosis; Mycoses; Nosocomial Infections; Nutrient; Operative Surgical Procedures; Organism; Outcome; Parasites; Pathway Analysis; Pathway interactions; Phenotype; Play; Procedures; Process; Pseudomonas aeruginosa; Refractory; Repression; Role; Saccharomyces cerevisiae; Salmonella enterica; Sepsis; Starvation; Sulfhydryl Compounds; Sulfides; Sulfites; Sulfur; Systemic infection; Temperature; Testing; Tissues; Unspecified or Sulfate Ion Sulfates; Up-Regulation; Validation; Virulence; Work; antimicrobial drug; auxotrophy; base; chemotherapy; drug development; drug sensitivity; enzyme pathway; fungus; genome sequencing; in vivo; mortality; mouse model; mutant; neonate; novel; pathogen; public health relevance; research study; response

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.

描述（由申请方提供）：真菌感染，最常见的是由白色念珠菌引起，目前是医院获得性血流感染的第四大原因，并且与归因死亡率最高相关。已经提出了许多策略来定义用于治疗系统性C的新代谢靶点。白色念珠菌感染然而，这些计划中的绝大多数都缺少对体内真菌代谢的理解。抗真菌药物开发的一个有希望的焦点是硫同化途径。在拟议的研究中，我们将使用遗传方法来定义生物体如何在播散性感染的动物模型中吸收硫。我们建议调查的重要性，导致硫酸盐还原为硫化物，硫化物纳入碳受体的途径，以及后者对半胱氨酸和蛋氨酸的合成通道。我们还将确定这些过程是否作为宿主内感染生态位的函数而变化。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）中的硫通量与人类中的硫通量在几个重要点上不同。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。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，范围从新生儿的持续治疗到骨髓移植，化疗和深部手术。这项拟议的研究将确定白色念珠菌，最常见的真菌病原体与医院感染，吸收和使用的基本营养素硫。初步研究加强了这一假设，即硫同化途径，其中包括独特的酶，没有哺乳动物的对应物，如果更好地理解，可以定义新的目标，为新的抗真菌疗法的发展。