A broad host-range Acinetobacter baumannii phage and its novel glycan receptor

About This Grant

PROJECT SUMMARY Acinetobacter baumannii (Ab) is a highly antibiotic resistant opportunistic pathogen that is a major source of hospital acquired infections. To combat its growing burden, there is an urgent need to find alternative methods of treatment, such as the use of bacteriophages (phages), termed phage therapy. Phage therapy has been used in isolated compassionate use cases of recalcitrant Acinetobacter infections, but is limited by the exquisitely narrow host range of most Ab phages. This narrow host range is in large part due to the highly variable capsule that occludes most phages from accessing the cell. Each phage typically carries a highly specialized capsule binding and depolymerase protein able to bind to and degrade a single capsule type. However, we recently isolated a broad host range Acinetobacter phage that attaches to an uncharacterized glycan that is accessible even when capsule is present. The glycan that the phage attaches to, which we have termed phage glycan receptor (PGR), was previously unknown even though it is found in almost all pathogenic Acinetobacter strains. The phage, termed StAb3, is also almost entirely uncharacterized, belonging to an unclassified taxon with few other phage relatives. StAb3 can infect about 90% of Ab strains, although it can only replicate efficiently in a subset of them. Combined, the discoveries of PGR and StAb3 present a unique opportunity to uncover fundamental biology while also advancing phage therapy or phage-derived therapeutics. To this end, we will investigate the structure and biosynthesis of PGR as well as its role in adherence and pathogenesis. In parallel, we will dissect the molecular interaction between the phage binding protein and PGR, as well as determine why even when this phage can infect most strains, it is often not able to replicate well. This study has the potential to transform the landscape of phage therapy and reveal unexplored aspects of Ab biology.