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Its effectiveness is increasingly challenged by the spread of genes coding for TMP-resistant dihydrofolate reductases: dfrA, and the lesser-known, evolutionarily unrelated dfrB. Despite recent reports of novel variants conferring high level TMP resistance (dfrB10 to dfrB21), the prevalence of dfrB is still unknown due to underreporting, heterogeneity of the analyzed genetic material in terms of isolation sources, and limited bioinformatic processing. In this study, we explored a coherent set of shotgun metagenomic sequences to quantitatively estimate the abundance of dfrB gene variants in aquatic environments. Specifically, we scanned sequences originating from influents and effluents of municipal sewage treatment plants as well as river-borne microbiomes. Our analyses reveal an increased prevalence of dfrB1, dfrB2, dfrB3, dfrB4, dfrB5, and dfrB7 in wastewater microbiomes as compared to freshwater. These gene variants were frequently found in genomic neighborship with other resistance genes, transposable elements, and integrons, indicating their mobility. By contrast, the relative abundances of the more recently discovered variants dfrB9, dfrB10, and dfrB13 were significantly higher in freshwater than in wastewater microbiomes. Moreover, their direct neighborship with other resistance genes or markers of mobile genetic elements was significantly less likely. Our findings suggest that natural freshwater communities form a major reservoir of the recently discovered dfrB gene variants. Their proliferation and mobilization in response to the exposure of freshwater communities to selective TMP concentrations may promote the prevalence of high-level TMP resistance and thus limit the future effectiveness of antimicrobial therapies.<\/jats:p>","DOI":"10.1038\/s41396-023-01460-7","type":"journal-article","created":{"date-parts":[[2023,6,27]],"date-time":"2023-06-27T09:02:31Z","timestamp":1687856551000},"page":"1455-1466","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":29,"title":["Trimethoprim resistance in surface and wastewater is mediated by contrasting variants of the<i>dfrB<\/i>gene"],"prefix":"10.1093","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6048-6984","authenticated-orcid":false,"given":"David","family":"Kneis","sequence":"first","affiliation":[{"name":"TU Dresden, Institute of Hydrobiology , 01062 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4865-0267","authenticated-orcid":false,"given":"Claud\u00e8le","family":"Lemay-St-Denis","sequence":"additional","affiliation":[{"name":"PROTEO, The Qu\u00e9bec Network for Research on Protein, Function, Engineering and Applications , Quebec, QC, Canada"},{"name":"CGCC, Center in Green Chemistry and Catalysis , Montr\u00e9al, QC, Canada"},{"name":"Department of Biochemistry & Molecular Medicine, University of Montr\u00e9al , Montr\u00e9al, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stella","family":"Cellier-Goetghebeur","sequence":"additional","affiliation":[{"name":"PROTEO, The Qu\u00e9bec Network for Research on Protein, Function, Engineering and Applications , Quebec, QC, Canada"},{"name":"CGCC, Center in Green Chemistry and Catalysis , Montr\u00e9al, QC, Canada"},{"name":"Department of Biochemistry & Molecular Medicine, University of Montr\u00e9al , Montr\u00e9al, QC H3T 1J4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5372-0923","authenticated-orcid":false,"given":"Alan X","family":"Elena","sequence":"additional","affiliation":[{"name":"TU Dresden, Institute of Hydrobiology , 01062 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas U","family":"Berendonk","sequence":"additional","affiliation":[{"name":"TU Dresden, Institute of Hydrobiology , 01062 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joelle N","family":"Pelletier","sequence":"additional","affiliation":[{"name":"PROTEO, The Qu\u00e9bec Network for Research on Protein, Function, Engineering and Applications , Quebec, QC, Canada"},{"name":"CGCC, Center in Green Chemistry and Catalysis , Montr\u00e9al, QC, Canada"},{"name":"Department of Biochemistry & Molecular Medicine, University of Montr\u00e9al , Montr\u00e9al, QC H3T 1J4, Canada"},{"name":"Chemistry Department, University of Montr\u00e9al , Montr\u00e9al, QC H2V 0B3, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefanie","family":"He\u00df","sequence":"additional","affiliation":[{"name":"TU Dresden, Institute of Microbiology , 01062 Dresden, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,6,27]]},"reference":[{"key":"2024011017455335600_CR1","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1002\/j.1875-9114.1981.tb03548.x","article-title":"Trimethoprim: mechanisms of action, antimicrobial activity, bacterial resistance, pharmacokinetics, adverse reactions, and therapeutic indications","volume":"1","author":"Gleckman","year":"1981","journal-title":"Pharmacother J Hum Pharmacol Drug Ther"},{"key":"2024011017455335600_CR2","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1099\/00222615-28-2-73","article-title":"The success of plasmid-encoded resistance genes in clinical bacteria. 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