Forecasting the dissemination of antibiotic resistance genes across bacterial genomes

Mostafa M H Ellabaan,Lejla Imamovic,Morten O A Sommer,Andreas Porse,Christian Munck

doi:10.1038/s41467-021-22757-1

Mostafa M H Ellabaan, Lejla Imamovic + Show 3 more

Open Access

https://doi.org/10.1038/s41467-021-22757-1

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Abstract

Antibiotic resistance spreads among bacteria through horizontal transfer of antibiotic resistance genes (ARGs). Here, we set out to determine predictive features of ARG transfer among bacterial clades. We use a statistical framework to identify putative horizontally transferred ARGs and the groups of bacteria that disseminate them. We identify 152 gene exchange networks containing 22,963 bacterial genomes. Analysis of ARG-surrounding sequences identify genes encoding putative mobilisation elements such as transposases and integrases that may be involved in gene transfer between genomes. Certain ARGs appear to be frequently mobilised by different mobile genetic elements. We characterise the phylogenetic reach of these mobilisation elements to predict the potential future dissemination of known ARGs. Using a separate database with 472,798 genomes from Streptococcaceae, Staphylococcaceae and Enterobacteriaceae, we confirm 34 of 94 predicted mobilisations. We explore transfer barriers beyond mobilisation and show experimentally that physiological constraints of the host can explain why specific genes are largely confined to Gram-negative bacteria although their mobile elements support dissemination to Gram-positive bacteria. Our approach may potentially enable better risk assessment of future resistance gene dissemination.

Highlights

Antibiotic resistance spreads among bacteria through horizontal transfer of antibiotic resistance genes (ARGs)
To identify putative horizontally transferred ARGs, we used a statistical test based on the assumption that genes transferred horizontally between two organisms are significantly more conserved than their 16S rRNA genes[6,7,12,13]
Annotated ARGs were considered horizontally transferable if pairwise alignment distances were significantly shorter for the resistance genes than for the 16S rRNA genes of their hosts

Summary

Introduction

Antibiotic resistance spreads among bacteria through horizontal transfer of antibiotic resistance genes (ARGs). Mobile genetic elements (MGEs) such as transposons and genes that encode enzymes that facilitate them such as integrases or recombinases often facilitate the initial mobilisation Such MGEs are capable of capturing ARGs from chromosomes and horizontally transferring them via a plasmid or a phage to other bacteria[7,8,9,10,11]. Analysis of mobile ARGs and their neighbouring mobilisation elements across 23,425 genomes found that phylogeny is another major variable shaping networks for resistance gene transfer[13]. This may be driven by biochemical interaction between acquired genes and the cellular machinery making the acquired genes less likely to function across phylogenetically distant hosts[14]. Despite the several studies proposed to identify the gene exchange networks[12,13,14,15] of ARGs, none so far has been proposed a systemic framework to identify the future dissemination of ARGs, considering current data available on the dissemination of ARGs and thier associated MGEs

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