The global β-lactam resistome revealed by comprehensive sequence analysis

Most antibiotic-resistance genes (ARGs) evolved in environmental microbes long before humanity’s antibiotic breakthrough, and widespread antibiotic use expedited the dissemination of ARGs among clinical pathogens. While widely discussed, the investigation of environmental ARG distributions lacks the scalability and taxonomic information necessary for a comprehensive analysis. Here, we present a global distribution of all five classes of β-lactamases among microbes and environments. We generated a β-lactamase taxonomy-environment map by identifying >113,000 β-lactamases across diverse bacterial phyla and environmental ecosystems. Remarkably abundant, their occurrence is only ∼2.6-fold lower than the essential recA gene in various environmental ecosystems, with particularly strong enrichment in wastewater and plant samples. The enrichment in plant samples implies an environment where the arms race of β-lactam producers and resistant bacteria occurred over millions of years. We uncover the origins of clinically relevant β-lactamases (mainly in ɣ-Proteobacteria) and expand beyond the previously suggested wastewater samples in plant, terrestrial, and other aquatic settings.