Dissemin is shutting down on January 1st, 2025

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National Academy of Sciences, Proceedings of the National Academy of Sciences, 25(115), 2018

DOI: 10.1073/pnas.1801646115

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Directed evolution of multiple genomic loci allows the prediction of antibiotic resistance

This paper is made freely available by the publisher.
This paper is made freely available by the publisher.

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Abstract

Significance Antibiotic development is frequently plagued by the rapid emergence of drug resistance. However, assessing the risk of resistance development in the preclinical stage is difficult. By building on multiplex automated genome engineering, we developed a method that enables precise mutagenesis of multiple, long genomic segments in multiple species without off-target modifications. Thereby, it enables the exploration of vast numbers of combinatorial genetic alterations in their native genomic context. This method is especially well-suited to screen the resistance profiles of antibiotic compounds. It allowed us to predict the evolution of resistance against antibiotics currently in clinical trials. We anticipate that it will be a useful tool to identify resistance-proof antibiotics at an early stage of drug development.