Connecting the Spatiotemporal Organization of Gut Bacterial Communities to the Emergence and Spread of Antibiotic Resistance

PROJECT SUMMARY Antibiotic resistant bacteria pose a global threat to human health and wellbeing. New strategies for combating resistance are urgently needed because current drug development pipelines are not keeping up with the dwindling supply of effective antibiotics. I propose to investigate and manipulate the ecology of antibiotic resistance acquisition and host-to-host transmission. Specifically, I will determine how the physical structure of bacterial communities within the intestine—which is a major reservoir of antibiotic resistant bacteria—affects the evolution of resistance traits and transmission of resistant cells. A motivation for this research direction is that antibiotic resistance fundamentally dependends on the spatial and temporal organization of host–microbe systems. For example, the sharing of resistance genes between bacteria through lateral gene transfer often requires cells to be in close proximity to one another. In addition, the transmission of resistant bacteria between hosts requires that they are physically displaced and expelled into the environment. Thus, altering the spatiotemporal organization of gut bacterial communities could be used to prevent and contain resistant bacteria before they become agents of infection. However, dissecting the spatially and temporally complex mechanisms governing antibiotic resistance is a significant challenge using current approaches. My solution to overcome this limitation is to combine synthetic biology, genetically engineered bacterial communities, and live imaging to track and control bacterial behavior inside the intestines of living animals. I will employ larval zebrafish as a vertebrate host model because they enable studies of host–microbe systems across scales of complexity, space, and time that are difficult to perform in mice or humans. Using this experimental approach, I previously discovered that intestinal flow, bacterial swimming motility, and sublethal antibiotics represent host, bacterial, and environmental factors, respectively, that can modulate the spatiotemporal organization and physiological landscape of gut bacteria. I will harness these factors and my experimental approach to address the following three hypotheses. First, I will test the hypothesis that the spatiotemporal organization of gut bacteria controls the acquisition and persistence of resistance traits within the intestine. Second, I will test the hypothesis that the spatiotemporal organization of gut bacteria regulates the transmission of antibiotic resistant cells between hosts. And third, I will test the hypothesis that bacteria coordinate both the acquisition of resistance traits and host-to-host transmission through specific genetic pathways. My proposed research has the potential to inspire ecology-based strategies for curtailing antibiotic resistance through the therapeutic manipulation of the intestinal microbiome’s physical structure. Such ecology-informed and antibiotic-free strategies would preserve the potency of current antibiotics for when they are needed most and avoid the unintended side effects of antibiotics on beneficial resident bacteria.