Genetic Reservoirs of Antibiotic Resistance in Environmental and Human Microbiota

Increasing rates of multi-drug resistance in human pathogens and declining antibiotic development pipelines are precipitating a worsening global infectious disease crisis. Steady use and abuse of antibiotics over the past century in food animals, humans and the environment has provided substantial selective pressure for enrichment of resistance genotypes in their associated microbiomes.  Antibiotic resistance determinants encoded on mobilizable elements can disseminate between these interacting microbial communities, which may all serve as reservoirs of resistance for pathogens.  We have applied high-throughput phenotypic assays with metagenomic functional selections to characterize reservoirs of transferable antibiotic resistance genes encoded by the microbiota of healthy humans as well as diverse soils. Hundreds of resistance genes we identify from these different microbial communities are identical to resistance genes found in major human pathogens, indicating recent genetic exchange between these microbes. We also find hundreds of functionally validated resistance genes which are genetically novel, but flanked by genes involved in horizontal gene transfer, including transposases and integrases. Together, these findings highlight the substantial antibiotic resistome encoded by microbes from diverse environments which is available for exchange with pathogens, with the potential to severely exacerbate the problems with clinical resistance.