Like Star Wars destroyers that send out pods on supply missions, some bacteria deploy small molecules called siderophores to collect the essential nutrient iron from hosts they infect. Two research groups now report a type of vaccine that programs animals’ immune systems to capture siderophores, killing invading bacteria by starving them of iron.
The strategy could become a new way to protect people from infections by Gram-negative bacteria, which use siderophores. Expanding the arsenal against these pathogens is an urgent necessity because many strains have become resistant to existing antibiotics. Antibiotic vaccines are already available for conditions such as meningitis, Haemophilus influenzae infections, pneumonia, and urinary tract infections, but some are toxic or only weakly protective, so scientists welcome new vaccine types.
Seven years ago, Raymond J. Bergeron and coworkers at the University of Florida induced mice to produce antibodies against a siderophore called vibriobactin used by Vibrio bacteria, which cause cholera (J. Med. Chem. 2009, DOI: 10.1021/jm900119q). However, they did not evaluate the ability of the antibodies to protect live animals from cholera because good animal models for Vibrio infection are not available.
Commenting on the new studies, Bergeron says the siderophore-based vaccine concept “still has a ways to go.” For example, some bacteria use multiple siderophores, so blocking just one may not work for all bacteria. Nevertheless, the new studies “are like absolution to us,” he says. “Coupled with what we did earlier, they show that this is a credible approach.”
Siderophores collect iron from bacterial hosts and then bring it back home by recognizing specialized receptors on bacterial cell membranes. To disrupt this process, Elizabeth M. Nolan of Massachusetts Institute of Technology, Manuela Raffatellu of the University of California, Irvine, and coworkers designed and synthesized derivatives of a Salmonella siderophore and conjugated it to a carrier protein that would induce an immune response in mice. Animals immunized with the conjugates developed antibodies that recognize and sequester the siderophores, killing Salmonella in the gut of infected mice (Proc. Natl. Acad. Sci.USA 2016, DOI: 10.1073/pnas.1606290113).
Harry L. T. Mobley’s group at the University of Michigan Medical School and coworkers immunized mice with two types of Escherichia coli siderophores conjugated to an immunogenic carrier protein. These siderophore-protein conjugates protected mice against urinary tract infections (Proc. Natl. Acad. Sci.USA 2016, DOI: 10.1073/pnas.1606324113). In fact, the siderophores were immunogenic enough on their own to elicit an immune response even when they were not protein-conjugated.
Bergeron says siderophore vaccines haven’t been taken seriously enough by research funding agencies. “People will pay attention now,” he says. “I hope the concept goes forward and does something for patients.”