Abstract
Antimicrobial resistance poses a great danger to humanity, in part due to the widespread horizontal gene transfer of plasmids via conjugation. Modeling of plasmid transfer is essential to uncovering the fundamentals of resistance transfer and for the development of predictive measures to limit the spread of resistance. However, a major limitation in the current understanding of plasmids is the incomplete characterization of the conjugative DNA transfer mechanisms, which conceals the actual potential for plasmid transfer in nature. Here, we consider that the plasmid‐borne origin‐of‐transfer substrates encode specific DNA structural properties that can facilitate finding these regions in large datasets and develop a DNA structure‐based alignment procedure for typing the transfer substrates that outperforms sequence‐based approaches. Thousands of putative DNA transfer substrates are identified, showing that plasmid mobility can be twofold higher and span almost twofold more host species than is currently known. Over half of all putative mobile plasmids contain the means for mobilization by conjugation systems belonging to different mobility groups, which can hypothetically link previously confined host ranges across ecological habitats into a robust plasmid transfer network. This hypothetical network is found to facilitate the transfer of antimicrobial resistance from environmental genetic reservoirs to human pathogens, which might be an important driver of the observed rapid resistance development in humans and thus an important point of focus for future prevention measures.
Highlights
Horizontal gene transfer of antimicrobial resistance (AMR) genes occurs via the processes of transformation and conjugation
The former mediates especially narrow range, intra-genus transfers 1,2,whereas the latter is implicated in a wider range of transfer hosts [3,4] and potentially enables AMR to overcome the toughest phylogenetic and ecological transmission barriers 5–10.the interaction between conjugative relaxase enzymes and their DNA origin-of-transfer substrates facilitates the majority of all AMR transfers in nature [11,12] and is especially important for ones related to human infection complications 13.the current knowledge on conjugative transfer mechanisms and systems [4,14,15,16] is unable to describe the unprecedented amount of observed horizontal transfer [7,8,12,17] that seems to transcend all transfer barriers between resistance reservoirs and human hosts . 5–7,9,10,12,13,18
High connectivity across habitats facilitates transfer of resistance genes to humans We explored how the increased potential for plasmid transfer between different host species (Fig 3) contributes to the connectivity across different environmental habitats and whether it facilitates the spread of AMR genes to humans
Summary
Horizontal gene transfer of antimicrobial resistance (AMR) genes occurs via the processes of transformation and conjugation. Zrimec 2019 sequence elements present and coevolving in the DNA substrate 4,even among plasmids belonging to a single species such as Staphylococcus aureus 32.OriT typing requires algorithms beyond simple sequence-based alignment 36,37,which can recognise and process more complex molecular motifs such as inverted repeats and hairpins [38,39,40] as well as underlying DNA physicochemical and conformational features These underpin key protein-DNA readout and activity mechanisms [4,41,42,43] as well as define conserved niches of structural variants that enable good resolution between Mob groups and subgroups 4.The use of DNA structural representations has led to improvements in algorithms for identification of other regulatory regions, such as promoters and replication origins [44,45,46,47,48].Despite this, instead of using tools that probe the actual relaxase-oriT interaction potential by identifying molecular properties that are the basis of such interactions, conventional approaches for oriT analysis still rely on mere nucleotide sequence-based methods 3 2,36,37. We evaluate if and how the uncovered fraction of oriTs helps to overcome the known barriers to horizontal gene transfer, by reconstructing and analysing the network of potential AMR transfers between different species and habitats, especially those from the environmental reservoir to the human flora
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