Development of bacteriophages as alternatives to antibiotics

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Bacteriophages (or phages) are viruses that specifically infect and kill bacteria. Most phages are comprised of an icosahedral head containing a double-stranded DNA genome, attached to a phage tail responsible for adhering to a surface receptor on the host bacterium. During infection the phage genome is delivered to the cell interior where phage proteins are expressed. The phage tail / host cell receptor interface is thought to be one of the most specific “lock and key” interactions in the biological world, and gives phages their exquisite specificity for bacterial cells. Molecular analysis of these mechanisms can provide insight into how phages defeat their bacterial hosts, and suggest successful strategies man can utilize to combat pathogenic bacteria. With the worldwide overuse of chemical antibiotics since the mid-20th century, we have recently observed a rapid increase in the number of bacteria presenting extreme antibiotic resistance, including bacteria of the genera Burkholderia and Stenotrophomonas. Therefore, the search for alternatives to antibiotics has gained importance, and the application of or treatment with phages has demonstrated promise, not only for human infections, but also for animal and plant diseases caused by bacteria. Numerous experimental studies have established phage treatment efficacy in both agricultural and clinical settings, and recently, instances of human lives being saved from pathogenic bacteria has been documented in North America. These results suggest that with further development, phages will become a useful addition to medicines available to complement or replace traditional antibiotics. The objective of this proposal is to examine phage mechanisms of attachment to bacterial receptors, and with this knowledge, optimize phages for application against highly antibiotic resistant bacteria. To decrease the evolution of phage resistance, multiple phages with different receptors will be combined, and phages that target virulence factors will promote anti-virulence in bacteria mutating to escape phage attack. Phages can be modified using molecular biology to eliminate problematic genes / proteins, and improved by adding genes that encode proteins that enhance activity (e.g. broaden host range, penetrate biofilms). Molecular characterization of the phage receptor-binding proteins, and the bacterium's surface receptors will provide important insights into the nature of the mechanisms involved in phage:bacterium interactions. The knowledge gained through this work will create opportunities to engineer phages against pathogenic and antibiotic resistant bacteria for a variety of novel biotechnological applications, including biosensors, relevant to agriculture, industry, and healthcare.