Year: 2012
Type: article
Abstract: Bacterial pathogens are becoming increasingly resistant to antibiotics. As an alternative therapeutic strategy, phage therapy reagents containing purified viral lysins have been developed against gram-positive organisms but not against gram-negative organisms due to the inability of these types of drugs to cross the bacterial outer membrane. We solved the crystal structures of a Yersinia pestis outer membrane transporter called FyuA and a bacterial toxin called pesticin that targets this transporter. FyuA is a β-barrel membrane protein belonging to the family of TonB dependent transporters, whereas pesticin is a soluble protein with two domains, one that binds to FyuA and another that is structurally similar to phage T4 lysozyme. The structure of pesticin allowed us to design a phage therapy reagent comprised of the FyuA binding domain of pesticin fused to the N-terminus of T4 lysozyme. This hybrid toxin kills specific Yersinia and pathogenic E. coli strains and, importantly, can evade the pesticin immunity protein (Pim) giving it a distinct advantage over pesticin. Furthermore, because FyuA is required for virulence and is more common in pathogenic bacteria, the hybrid toxin also has the advantage of targeting primarily disease-causing bacteria rather than indiscriminately eliminating natural gut flora.
Language: English
Subfield: Ecology
Field: Environmental Science
Domain: Physical Sciences
Open Access status: bronze
Funders: U.S. Department of Energy, Burroughs Wellcome Fund, National Institutes of Health, Office of Science, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Basic Energy Sciences, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Argonne National Laboratory
Awards: G102163711, G107546177, G1286251239, G1313983767, G1664757510, G1678787968, G1756342139, G18202666, G2123841078, G2287611682, G2479607971, G262962599, G2887060908, G3075337988, Building Interdisciplinary Careers in Women's Health, G426311843, G498139845, G5106849484, G5387317844, G5607048534, G572720644, G6848031779, G6918803902, G6967276973, G7368700025, G7583137537, G9000109234, G969889393, G993149817
OpenAlex ID: W2011957174