期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2016
卷号：113
期号：47
页码：13462-13467
DOI：10.1073/pnas.1606290113
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceGram-negative pathogens represent a major public health issue. With increases in antibiotic resistance and the limited availability of preventive strategies, new ways are needed to target these bacteria. Here, we propose a narrow-spectrum immunization strategy to block the ability of a gastrointestinal pathogen to acquire the essential metal nutrient iron. This approach involves the chemical synthesis of bacterial iron chelators, known as siderophores, and their conjugation to immunogenic carrier proteins. Mice immunized with these compounds developed antibodies against siderophores in the intestine, which hindered proliferation of the gut pathogen Salmonella. Because similar but distinct molecules are secreted by many bacterial and fungal pathogens, this synthesis and immunization strategy could be applied to a broad range of infectious agents. Infections with Gram-negative pathogens pose a serious threat to public health. This scenario is exacerbated by increases in antibiotic resistance and the limited availability of vaccines and therapeutic tools to combat these infections. Here, we report an immunization approach that targets siderophores, which are small molecules exported by enteric Gram-negative pathogens to acquire iron, an essential nutrient, in the host. Because siderophores are nonimmunogenic, we designed and synthesized conjugates of a native siderophore and the immunogenic carrier protein cholera toxin subunit B (CTB). Mice immunized with the CTB-siderophore conjugate developed anti-siderophore antibodies in the gut mucosa, and when mice were infected with the enteric pathogen Salmonella, they exhibited reduced intestinal colonization and reduced systemic dissemination of the pathogen. Moreover, analysis of the gut microbiota revealed that reduction of Salmonella colonization in the inflamed gut was accompanied by expansion of Lactobacillus spp., which are beneficial commensal organisms that thrive in similar locales as Enterobacteriaceae. Collectively, our results demonstrate that anti-siderophore antibodies inhibit Salmonella colonization. Because siderophore-mediated iron acquisition is a virulence trait shared by many bacterial and fungal pathogens, blocking microbial iron acquisition by siderophore-based immunization or other siderophore-targeted approaches may represent a novel strategy to prevent and ameliorate a broad range of infections.
关键词：siderophore ; immunization ; iron ; Salmonella ; microbiota
