A multi-scale approach to understanding the mechanisms of mobile DNA driven antimicrobial resistance transmission (JumpAR)

Transmission

Antimicrobial resistance (AMR) spreads at an alarming pace resulting in continuous emergence of more virulent pathogens and multidrug-resistant ‘superbugs’.

Ongoing project

Mobile genetic elements (MGE) provide a major mechanism to transfer AMR genes in hotspots of microbial interaction, including the bacterial communities in the human gut. However, the dynamics and mechanisms of movement of such ‘jumping genes’ are poorly understood. It is unclear how often they move, which natural and manmade compounds influence their movement, and how their movement occurs at the molecular level.

Here we propose (i) to annotate and characterize MGEs in available bacterial genomes and metagenomes in order to characterize their genetic cargos and dynamics of transfer; (ii) to study the impact of antibiotic treatment on MGE-mediated gene transfer in human patients with antibiotic resistant infections; (iii) to analyse the influence of natural microbial compounds and diverse clinically applied drugs on AMR transmission; and (iv) to dissect the structure and functioning of the underlying molecular machinery. This work will elucidate AMR transfer at all scales from atomic resolution through bacterial and animal models to gut ecosystems in human patients individually and at the population level.

To achieve these ambitious aims, our multidisciplinary consortium brings together leading scientists with complementary expertise in metagenomics, infection biology, infection medicine, molecular genetics, chemical biology, and structural biology. By drawing on available genomic and metagenomic data, we will gain a global picture of the prevalence and distribution of MGEs, their AMR gene cargos, and transmission potential. Using clinical samples, including available data and a novel specialized cohort, we will chart the effects of antibiotics and other human drugs on MGE-borne AMR transmission, which will enable predictions on the likelihood of transfer in different settings. Using in vivo and in vitro models, we will obtain molecular level insights into the mechanisms and extent of active AMR transmission. Using unbiased highthroughput screening (HTS) in bacterial cultures, we will scout unanticipated environmental modulators of AMR transmission, which we will validate in animal models and identify their mode of action in in vitro tests and structure-function studies. Integration of these insights will vastly expand our knowledge on the mechanisms and dynamics of MGE-borne AMR dissemination, opening doors to the development of novel intervention strategies and preventive measures aimed at reducing active transfer of AMR genes.

In particular, our genomic surveys will help us develop risk assessment approaches relying on accurate prediction of AMR gene mobility, and our data on transfer enhancers and inhibitors will allow to design revised treatment guidelines for AMR colonized patients to prevent further transmission of resistance. Furthermore, we expect that the knowledge acquired here will lead to additional clinically relevant outcomes on the longer term, including design of specific inhibitors to prevent MGE-mediated AMR transfer, and development of diagnostic tools for AMR gene mobility.

Project partners

  • Orsola Barabas, European Molecular Biology Laboratory, Germany (Coordinator)
  • Peer Bork, European Molecular Biology Laboratory, Germany
  • Maria Fällman, Umeå University, Sweden
  • Johan Normark, Norrlands University Hospital, Sweden
  • Gerard Wright, McMaster University, Canada

Antimicrobial resistance (AMR) is one of the greatest global health challenges. It spreads rapidly, constantly generating more dangerous bacteria. Mobile genetic elements, segments of DNA that can move between bacterial cells, are a major route for resistance transfer in microbial communities. How often such ‘jumping genes’ move, which natural and man-made compounds influence them, and how they move at the molecular level is not understood.

Here, we aim to survey mobile DNA elements, identify their resistance cargos, and how they move between different bacteria. Drawing on genome and metagenome sequencing data, we will gain a global picture of the abundance and distribution of mobile genetic elements, their resistance gene cargos, and transmission potential. In a dedicated clinical study, we will chart the effects of antibiotics and other human drugs on mobile DNA-mediated resistance spreading. In addition, we will follow AMR transfer in animal models and scout unanticipated modulators of AMR transmission in unbiased high-throughput screens with common human drugs and natural compounds. Moreover, we will obtain insights into the structure and functioning of the molecular machinery involved in AMR transmission.

Using biochemistry and structural biology, we will elucidate the organization and chemical action of the molecular machinery involved in resistance gene mobilization. Our collective results will vastly expand knowledge on mobile DNA-driven resistance spreading, opening doors to the development of novel intervention, risk assessment and preventive strategies against resistance spreading.

Publications

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