STRUCTURAL ANALYSIS OF SIDEROPHORE BIOSYNTHESIS: AIDS ANTIBIOTICS

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。我们工作的长期目标是详细了解铜绿假单胞菌产生铁载体的分子机制。铁载体碧蛋白和焦蛋白是这种有机体的毒力因子；如果铁载体的生产受到干扰，细菌就无法获得在限制铁的环境(如人类宿主)中生存所需的铁。众所周知，铜绿假单胞菌对抗生素具有耐药性，能够在免疫功能低下的患者和囊性纤维化患者的肺部定植。其他致命细菌利用铁载体在人体组织中定居，包括鼠疫细菌(鼠疫耶尔森氏菌)和霍乱细菌(霍乱弧菌)。因此，有关生物合成酶的结构信息不仅可以为合理设计治疗CF和癌症、艾滋病和烧伤患者免疫抑制引起的继发感染的抗生素提供新的抗微生物靶点，而且可以为打击生物恐怖主义提供新的抗微生物靶点。我们在子项目中的工作重点是鸟氨酸的衍生化和与吡咯菌素的结合。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goal of our work is to understand in atomic detail the molecular mechanisms of siderophore production by Pseudomonas aeruginosa. The siderophores pyochelin and pyoverdin are virulence factors for this organism; if siderophore production is disrupted, the bacteria cannot acquire the iron required for survival in iron limiting environments such as the human host. Pseudomonas aeruginosa is notoriously antibiotic resistant and is able to colonize immuno-compromised patients and the lungs of patients with cystic fibrosis. Other deadly bacteria use siderophores in colonization of human tissues including plague bacteria (Yersinia pestis) and cholera bacteria (Vibrio cholerae). Therefore, structural information about the biosynthetic enzymes of pyochelin and pyoverdin may provide new anti-microbial targets not only for the rational drug design of antibiotics for CF therapy and secondary infections due to immunodepression in cancer, AIDS and burn patients, but also for the fight against bioterrorism. Our work in the subproject focuses on ornithine derivatization and incorporation into pyoverdin.