Siderophores and Iron Acquisition

Nearly all species of bacteria require iron for electron transport and as a cofactor for central metabolic enzymes. Under iron-limiting conditions, many species of bacteria secrete small iron-chelating molecules termed ‘siderophores’ that bind iron with an extremely high affinity, essentially stealing iron directly from the host-binding proteins. Outer membrane siderophore receptor proteins (SRPs®) bind the iron-bound siderophores and interact with other membrane-associated proteins to internalize iron. Additional porins, which form channels through the bacterial membrane, are involved with the import of small molecules.

Other bacterial iron uptake systems include receptors that specifically bind transferrin, lactoferrin, heme or hemoglobin and obtain iron directly from these molecules. Many pathogenic bacteria express their iron uptake systems in vivo, and in some cases, specific components of the iron uptake systems have been shown to be required for establishing successful infections.

When a pathogen infects a mammalian host, it encounters a hostile environment due to factors such as limited oxygen availability, the presence of antimicrobial enzymes, pH stress, and nutrient restriction. Iron is one of the primary nutrients in limited supply during microbial invasion of a mammalian host. Some of the major contributing factors to this iron limitation are the intracellular storage of iron by ferritin and the circulation of host iron-binding proteins such as transferrin and lactoferrin, the host response to microbial infection further exacerbates iron limitation by reducing the serum concentration of iron and transferrin.

Syntiron’s patented vaccine technology is based on the use of defined bacterial cell surface components as target antigens for vaccine and immunotherapeutic development. While this technology has been successfully established for use in veterinary healthcare, Syntiron is currently developing the technology for several areas of human healthcare.

Syntiron is leveraging this concept to generate vaccines composed of bacterial iron uptake system components which train the immune system to recognize a set of relevant outer surface components immediately upon invasion. Furthermore, therapies generated in response to these iron uptake system components have shown promise for certain at-risk populations to protect against bacterial infection.

Our antimicrobial products are based on proprietary SRP® Technology, which has shown exemplary disease protection in a wide variety of animals, including laboratory studies and large field tests in the agriculture industry. The platform vaccine technology is being tailored for human health protection using advanced bioinformatic, proteomic and molecular techniques in order to understand precisely how our vaccines work, and to maximize their safety and efficacy. Currently, we are developing both vaccines and antibody-based immunotherapeutic agents for the prevention and treatment of human bacterial diseases of relevance to hospital infections, biodefense, travelers and food safety.

Active Immunization Using SRP® Antigens

There are a number of essential features regarding these specialized transport proteins that open a window of opportunity for disease prevention through active immunization. These specialized transport proteins are exposed on the outer membrane of the bacterium, making them susceptible to circulating antibodies produced by the host.

Active immunization against SRPs® results in disabling bacterial cell wall receptors required for acquisition of elemental iron, which is an essential bacterial nutrient for metabolism and survival in host animal tissues.

Antibody-mediated response to these surfaced exposed outer membrane proteins can increase opsonization, that is, increase macrophage activity resulting in increased phagocytosis and induce complement-mediated bacterial lysis.

Biochemical and genetic analysis has shown these outer membrane proteins (OMPs) to be highly conserved and expressed in high copy number; e.g., OmpA, OmpC and OmpF are present at 100,000 copies per bacterial cell.

A number of these porins demonstrate immuno-regulatory activity, acting as T and/or B cell activators which stimulate the synthesis of various cytokines or activate intracellular signaling pathways, thus enhancing the protective efficacy of the vaccine composition.