STRUCTURAL ANALYSIS OF SIDEROPHORE BIOSYNTHESIS: AIDS ANTIBIOTICS

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。我们工作的长期目标是了解铜绿假单胞菌铁载体生产的分子机制的原子细节。铁载体绿脓菌螯铁蛋白和绿脓菌荧光素是这种生物的毒力因子;如果铁载体的生产被破坏，细菌就不能获得在铁限制环境（如人类宿主）中生存所需的铁。铜绿假单胞菌是众所周知的抗生素耐药性，并能够定殖免疫功能低下的患者和囊性纤维化患者的肺部。其他致命细菌利用铁载体在人体组织中定植，包括鼠疫菌（鼠疫耶尔森氏菌）和霍乱菌（霍乱弧菌）。因此，绿脓菌螯铁蛋白和绿脓菌荧光素的生物合成酶的结构信息不仅可以为用于CF治疗和由于癌症、AIDS和烧伤患者中的免疫抑制引起的继发感染的抗生素的合理药物设计提供新的抗微生物靶标，而且还可以为对抗生物恐怖主义提供新的抗微生物靶标。我们在子项目中的工作重点是鸟氨酸衍生化和掺入绿脓菌荧光素。

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.