Characterizing novel Beta-lactamases from metagenomic samples: insights into the evolution of antimicrobial resistance from the environment towards human-associated pathogens

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PROJECT SUMMARY β-Lactamases are the most widespread resistance mechanism to β-lactam antibiotics. Of particular concern are a group of β-lactamases known as carbapenemases, named for their ability to destroy our newest β-lactam antibiotics, the carbapenems. The rise of carbapenem resistance is a recent global trend that has resulted in pan-national fear. An interesting approach to understand carbapenem resistance and how it evolves is through quantitative analysis of non-pathogenic microorganisms found in the environment. Analysis of these microorganisms offers the intriguing possibility of predicting how antibiotic resistance may evolve and provides clinicians with an “early warning” system for the advent of novel resistance mechanisms in pathogenic bacteria. Previous research has shown that the soil is an excellent repository for many β-lactamases, especially carbapenemases. The main part of the project will be the study of a collection of metagenome-origin β-lactamases isolated from Alaskan soil, named LRA (for “β-lactam resistance from Alaska”). This metagenomic approach will be expanded and applied to the analysis of soil samples from Antarctica to identify β-lactamase-mediated resistance in different isolated regions. Identified environmental β-lactamases will be characterized using a multi-pronged approach involving phenotypic, molecular, biochemical and structural techniques. Specifically, results from this comprehensive analysis will allow us to assess the evolutionary routes of β-lactamases found among clinical pathogens that plague human health today, and to evaluate novel niches of potentially unexplored genes that could be recruited by these pathogens.