Building a Comprehensive Discovery System for Understanding Bacterial Multidrug Resistance and Pathogenesis Using Tn7-like Elements

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Project Summary / Abstract Our large-scale bioinformatics analyses of bacterial genomes indicate that 10-20% contain diverse active Tn7-like elements. We find that many previously enigmatic pathogenicity islands are explained by these elements suggesting they are important and underappreciated vehicles of exchange across diverse bacterial species. In this grant, we will develop computational methods to enumerate, classify and characterize Tn7- like elements which will provide a comprehensive understanding of their roles in the evolution of pathogenesis and acquisition of antibiotic resistance in bacteria. This includes determining the loci where Tn7-like elements form genomic islands, the genetic information they mobilize, and the gene products associated with mobilization. We will use this information to develop new tools based on these elements to efficiently engineer diverse types of important bacteria. This will include tools to insert genetic information into conserved neutral sites in the chromosomes of bacteria at high efficiency, including new and emerging pathogens and commensal bacteria that lack efficient genetic tools. Relevance to Public Health: We will determine the molecular mechanisms that allow the evolution of emerging pathogens and multi drug resistant bacteria though the transfer of genetic information. This will lead to better treatments and strategies to limit the evolution of more serious pathogens. Public health will also be served because we will be developing an important new genome modification technique that will be broadly applicable in bacteria and possibly other kinds of organisms.