Community organizing: Harnessing the interactions of the microbiome as a basis for novel therapeutic strategies

Jackson Laboratory, Bar Harbor ME

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Title: Community organizing: Harnessing the interactions of the microbiome as a basis for novel therapeutics Next-generation antibiotics and antimicrobials necessitate new design principles that incorporate information about both a pathogen's unique genetic susceptibilities and virulence factors as well as information about its surrounding microbial community. This community, the microbiome, contains both beneficial symbionts and a genetic reservoir for horizontal exchange of antibiotic resistance or virulence genes. An effective therapeutic design would precisely target pathogens and disease-enhancing genes yet spare the healthy diversity of beneficial microbes. However, the `parts list' that defines potential targets in the pathogen of interest and the contextual microbiome are incompletely defined given the large uncharacterized space, or microbial `dark matter' that persists in microbiome characterization studies. My Aims 1 and 2 propose both computational (iterative binning & assembly) and experimental approaches (immunomagnetic separation of human cells prior to single cell sequencing) whose goal is to enable a deep interrogation of this dark matter. These approaches will provide new depth to our knowledge of the genes and genomes of the skin's microbial communities, creating an expanded `parts' lists of genes and interspecies interactions networks that will inform rational design. In turn, these genetic reconstructions can be used for the basis for synthetic design. In my third aim, I propose creation of a synthetic phage vehicle that delivers CRISPR/Cas genome modification tools to genetically manipulate or kill methicillin-resistant Staphylococcus aureus, a major human pathogen, within the context of a mixed microbial community. More broadly, completion of these aims will see the creation of a generalized toolkit that can be used to engineer a large variety of pathogens and microbial communities.