ca994388ea37c73796d5a63f620966c4 pmc_11350921.pdf ed2c50f4924fe94e5c2e9b6d1f1cc7337d4b013c pmc_11350921.pdf 5f5cb2973aebc61450b7ccee572f96b6471c9744d4dc3d989d9b4611dc412631 pmc_11350921.pdf Title: Global Variation in Escherichia coli mcr-1 Genes and Plasmids from Animal and Human Genomes Following Colistin Usage Restrictions in Livestock Subject: Antimicrobial resistance (AMR) is a significant global health threat, with multidrug-resistant (MDR) bacterial clones becoming a major concern. Polymyxins, especially colistin, have reemerged as last-resort treatments for MDR Gram-negative infections. However, colistin use in livestock has spread mobile colistin resistance (mcr) genes, notably mcr-1, impacting human health. In consequence, its livestock use was banned in 2017, originating a natural experiment to study bacterial adaptation. The aim of this work was to analyse the changes in the mcr-1 genetic background after colistin restriction across the world. This study analyses 3163 Escherichia coli genomes with the mcr-1 gene from human and livestock hosts, mainly from Asia (n = 2621) and Europe (n = 359). Genetic characterisation identifies IncI2 (40.4%), IncX4 (26.7%), and multidrug-resistant IncHI2 (18.8%) as the most common plasmids carrying mcr-1. There were differences in plasmids between continents, with IncX4 (56.6%) being the most common in Europe, while IncI2 (44.8%) was predominant in Asia. Promoter variants related to reduced fitness costs and ISApl1 showed a distinct pattern of association that appears to be associated with adaptation to colistin restriction, which differed between continents. Thus, after the colistin ban, Europe saw a shift to specialised mcr-1 plasmids as IncX4, while ISApl1 decreased in Asia due to changes in the prevalence of the distinct promoter variants. These analyses illustrate the evolution of mcr-1 adaptation following colistin use restrictions and the need for region-specific strategies against AMR following colistin restrictions. Keywords: antimicrobial resistance; colistin; mcr-1; ISApl1; promoter variants; fitness cost; Escherichia coli Author: Biel Garcias, Mayra Alejandra Flores, Mercedes Fernández, William Monteith, Ben Pascoe, Samuel K. Sheppard, Marga Martín, Martí Cortey and Laila Darwich Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Mon Aug 12 08:18:17 2024 CEST ModDate: Mon Aug 12 09:17:22 2024 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 12 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1988297 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- SSNIUI+VnURWPalladioL-Bold Type 1 Custom yes yes yes 10 0 KHTCXD+URWPalladioL-Bold Type 1 Custom yes yes yes 16 0 WCNRVV+URWPalladioL-Roma Type 1 Custom yes yes yes 22 0 MGVXSN+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 YDCPFF+URWPalladioL-BoldItal Type 1 Custom yes yes yes 32 0 QKLWSR+VnURWPalladioL Type 1 Custom yes yes yes 37 0 YYFPCJ+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 54 0 EMCIAJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 81 0 EMCIAK+PalatinoLinotype CID TrueType Identity-H yes yes yes 84 0 EMCIAL+PalatinoLinotype TrueType WinAnsi yes yes no 90 0 EMCIAN+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 93 0 EMCIFO+PalatinoLinotype TrueType MacRoman yes yes no 96 0 EMCIAJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 110 0 EMCIAK+PalatinoLinotype CID TrueType Identity-H yes yes yes 113 0 EMCIAL+PalatinoLinotype TrueType WinAnsi yes yes no 119 0 EMCIAN+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 122 0 EMCIFO+PalatinoLinotype TrueType MacRoman yes yes no 125 0 EMCIAJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 140 0 EMCIAK+PalatinoLinotype CID TrueType Identity-H yes yes yes 143 0 EMCIAL+PalatinoLinotype TrueType WinAnsi yes yes no 149 0 EMCIAM+PalatinoLinotype,Italic CID TrueType Identity-H yes yes yes 152 0 EMCIAN+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 158 0 EMCIFO+PalatinoLinotype TrueType MacRoman yes yes no 161 0 EMCIAJ+PalatinoLinotype,Bold TrueType WinAnsi yes yes no 175 0 EMCIAK+PalatinoLinotype CID TrueType Identity-H yes yes yes 178 0 EMCIAL+PalatinoLinotype TrueType WinAnsi yes yes no 184 0 EMCIAN+PalatinoLinotype,Italic TrueType WinAnsi yes yes no 187 0 EMCIFO+PalatinoLinotype TrueType MacRoman yes yes no 190 0 SAUAIP+CMSY10 Type 1 Builtin yes yes yes 197 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-09-19 02:49:26 CEST RepresentationInformation: pmc_11350921.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-09-18 02:31:05 CEST Size: 1988297 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 434 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: mcr-1-Positive E. coli Are Globally Distributed in Humans and Livestock Destination: subsection.2.1 Item: Title: IncI2 and IncX4 Are Specialized for mcr-1 While IncHI2 Is a MDR Destination: subsection.2.2 Item: Title: Mcr-1 Promoter Variants Are Associated with Specific Plasmids and Insertion Elements Destination: subsection.2.3 Item: Title: IncI2 and IncX4 Plasmids Predominate in Asia and Europe, Respectively Destination: subsection.2.4 Item: Title: Different Genome Adaptations Occur Following Withdrawal of Colistin in Europe and Asia Destination: subsection.2.5 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Children: Item: Title: Isolate Genomes Destination: subsection.4.1 Item: Title: Multilocus Sequence Typing and AMR Genes General Detection Destination: subsection.4.2 Item: Title: Genomic Context of mcr-1 Gene Destination: subsection.4.3 Item: Title: Data Analysis and Visualization Destination: subsection.4.4 Item: Title: Conclusions Destination: section.5 Item: Title: References Destination: appendix.A. Info: Title: ぇぬはぢちぬ〠ざちひどちぴどはの〠どの〠ぅびっとづひどっとどち〠っはぬど゠ねっひ〭〱〠ぇづのづび〠ちのつ〠ぐぬちびねどつび〠てひはね〠ぁのどねちぬ〠ちのつ〠えふねちの〠ぇづのはねづび〠うはぬぬはぷどので〠ぃはぬどびぴどの〠さびちでづ〠げづびぴひどっぴどはのび〠どの〠がどぶづびぴはっに Author: Biel Garcias, Mayra Alejandra Flores, Mercedes Fernández, William Monteith, Ben Pascoe, Samuel K. Sheppard, Marga Martín, Martí Cortey and Laila Darwich Subject: Antimicrobial resistance (AMR) is a significant global health threat, with multidrug-resistant (MDR) bacterial clones becoming a major concern. Polymyxins, especially colistin, have reemerged as last-resort treatments for MDR Gram-negative infections. However, colistin use in livestock has spread mobile colistin resistance (mcr) genes, notably mcr-1, impacting human health. In consequence, its livestock use was banned in 2017, originating a natural experiment to study bacterial adaptation. The aim of this work was to analyse the changes in the mcr-1 genetic background after colistin restriction across the world. This study analyses 3163 Escherichia coli genomes with the mcr-1 gene from human and livestock hosts, mainly from Asia (n = 2621) and Europe (n = 359). Genetic characterisation identifies IncI2 (40.4%), IncX4 (26.7%), and multidrug-resistant IncHI2 (18.8%) as the most common plasmids carrying mcr-1. There were differences in plasmids between continents, with IncX4 (56.6%) being the most common in Europe, while IncI2 (44.8%) was predominant in Asia. Promoter variants related to reduced fitness costs and ISApl1 showed a distinct pattern of association that appears to be associated with adaptation to colistin restriction, which differed between continents. Thus, after the colistin ban, Europe saw a shift to specialised mcr-1 plasmids as IncX4, while ISApl1 decreased in Asia due to changes in the prevalence of the distinct promoter variants. These analyses illustrate the evolution of mcr-1 adaptation following colistin use restrictions and the need for region-specific strategies against AMR following colistin restrictions. 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