Siderophore-based immunization strategy to inhibit growth of enteric pathogens

Abstract

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.

Biotechnology of siderophores in high-impact scientific fields

“…Siderophores have been used to develop vaccines and have been covered extensively (80)(81)(82)(83)(84). Bergeron and colleagues reported the use of a vibriobactin analogue linked to either ovalbumin (OVA) or bovine serum albumin (BSA) and their ability to promote antibody production in mice (85).…”

A New Way to Beat Intestinal Pathogens

“…Another iron-based antimicrobial approach exploits siderophores that have been naturally or synthetically conjugated to antibiotics, tricking microbes into taking up the antibiotic along with the siderophore [3]. A third siderophore-based strategy, priming the host to make anti-siderophore antibodies that may prevent microbes from acquiring iron, has recently taken a giant leap forward [4]. …”

“…This and other observations suggested that vaccinating against siderophores may confer protection against pathogens that require them. Recently a team of microbiologists and chemists took the next major step [4]. Sassone-Corsi et al .…”

“…Next, the Sassone-Corsi team [4] examined whether vaccination confers resistance to infection with Salmonella . Five to eight weeks after immunization, they pre-treated mice orally with the antibiotic streptomycin to increase susceptibility to Salmonella [8].…”

“…Five to eight weeks after immunization, they pre-treated mice orally with the antibiotic streptomycin to increase susceptibility to Salmonella [8]. They then challenged orally with 10 9 bacteria [4]. By the fourth day after infection, the CTB-Ent-immunized mice contained 10-fold fewer Salmonella in their intestines.…”