Category: EMBARK

Published paper: Modeling antibiotic resistance gene emergence

Last week, a paper resulting from a collaboration with Stefanie Heß and Viktor Jonsson was published in Environmental Science & Technology. In the paper, we build a quantitative model for the emergence of antibiotic resistance genes in human pathogens and populate it using the few numbers that are available on different processes (bacterial uptake, horizontal gene transfer rates, rate of mobilization of chromosomal genes, etc.) in the literature (1).

In short, we find that in order for the environment to play an important role in the appearance of novel resistance genes in pathogens, there needs to be a substantial flow of bacteria from the environment to the human microbiome. We also find that most likely the majority of resistance genes in human pathogens have very small fitness costs associated with them, if any cost at all.

The model makes three important predictions:

  1. The majority of ARGs present in pathogens today should have very limited effects on fitness. The model caps the average fitness impact for ARGs currently present in human pathogens between −0.2 and +0.1% per generation. By determining the fitness effects of carrying individual ARGs in their current hosts, this prediction could be experimentally tested.
  2. The most likely location of ARGs 70 years ago would have been in human-associated bacteria. By tracking ARGs currently present in human pathogens across bacterial genomes, it may be possible to trace the evolutionary history of these genes and thereby identify their likely hosts at the beginning of the antibiotic era, similar to what was done by Stefan Ebmeyer and his colleagues (2). What they found sort-of corroborate the findings of our model and lend support to the idea that most ARGs may not originate in the environment. However, this analysis is complicated by the biased sampling of fully sequenced bacterial genomes, most of which originate from human specimens. That said, the rapid increase in sequencing capacity may make full-scale analysis of ARG origins using genomic data possible in the near future, which would enable testing of this prediction of the model.
  3. If the origins of ARGs currently circulating in pathogens can be established, the range of reasonable dispersal ability levels from the environment to pathogens narrows dramatically. Similarly, if the rates of mobilization and horizontal transfer of resistance genes could be better determined by experiments, the model would predict the likely origins more precisely. Just establishing a ball-park range for the mobilization rate would dramatically restrict the possible outcomes of the model. Thus, a more precise determination of any of these parameters would enable several more specific predictions by the model.

This paper has a quite interesting backstory, beginning with me having leftover time on a bus ride in Madison (WI), thinking about whether you could quantize the conceptual framework for resistance gene emergence we described in our 2018 review paper in FEMS Reviews Microbiology (3). This spurred the first attempt at such a model, which then led to Stefanie Heß and me applying for support from the Centre for Antibiotic Resistance Research at the University of Gothenburg (CARe) to develop this idea further. We got this support and Stefanie spent a few days with me in Gothenburg developing this idea into a model we could implement in R.

However, at that point we realized we needed more modeling expertise and brought in Viktor Jonsson to make sure the model was robust. From there, it took us about 1.5 years to refine and rerun the model about a million times… By the early spring this year, we had a reasonable model that we could write a manuscript around, and this is what now is published. It’s been an interesting and very nice ride together with Stefanie and Viktor!

References

  1. Bengtsson-Palme J, Jonsson V, Heß S: What is the role of the environment in the emergence of novel antibiotic resistance genes? A modelling approach. Environmental Science & Technology, Article ASAP (2021). doi: 10.1021/acs.est.1c02977 [Paper link]
  2. Ebmeyer S, Kristiansson E, Larsson DGJ: A framework for identifying the recent origins of mobile antibiotic resistance genes. Communications Biology 4 (2021). doi: 10.1038/s42003-020-01545-5
  3. Bengtsson-Palme J, Kristiansson E, Larsson DGJ: Environmental factors influencing the development and spread of antibiotic resistance. FEMS Microbiology Reviews, 42, 1, 68–80 (2018). doi: 10.1093/femsre/fux053 [Paper link]

More podcasting: The AMR Studio

Not only did we release the most recent episode of the lab’s podcast this weekend. Today, the episode of The AMR Studio where I’m interviewed by Eva Garmendia of the Uppsala Antibiotic Center was put online. We talk mostly about antibiotic resistance in the environment and the role that the EMBARK program can play in mitigating environmental resistance. I think it’s a nice listen (recorded in the beautiful world pre-covid-19). Find it where you find podcasts (e.g. Apple or Spotify).

And like that, the world had changed

I guess it hasn’t passed anyone by that we are under a global lockdown (although to very different degrees – Sweden, where we’re based, has a pretty relaxed attitude to quarantining people (1), so it could be worse for us, I guess). In any case, the novel coronavirus has forced the lab to largely work from home and has upended essentially all my plans for this spring, expect for writing grant applications (which I have done a lot).

First of all, I want to thank my fellow lab members for holding out strongly in these trying times. They have consistently shown that they are the best co-workers I could ask for, and have kept calm even when anxiety hits. Thanks a lot for that. I also would like to thank the university for providing rather clear guidance on how to handle different issues that come up in these time of crisis.

With that said, I am also sad to say that there will not be a Microbiome & Probiotics Collaboration Forum in Rotterdam on May 18-20. Instead that meeting has been postponed to early December. Similarly, I will not be in Helsinki next week to talk about EMBARK. That workshop will instead, hopefully, take place on August 28. And the same story goes for the NordicMappingAMR organised by the Swedish Medical Products Agency, which will take place at a later date (I am not sure exactly when this is planned yet).

These are trying times for all of us. I hope that you stay healthy and take care of your loved ones – particularly the elderly, but not unnecessarily visiting them. My grandparents (aged 93 and 95) have started FaceTiming us, so I guess some good things come out of this mess as well. We will come out of this crisis stronger, eventually.

Footnotes

  1. There are many things I could say about the Swedish strategy regarding covid-19, but this is not really the forum. In very brief, though, I have quite some faith in that the Swedish Public Health Agency is doing a decent job. Mistakes have been made (particularly early in the pandemic) and I am slightly anxious whether the Swedish strategy will play out as well as in other countries in Northern Europe, but right now data suggest that we are doing reasonable fine. I might return to this issue in another post if time permits.

Conferences and a PhD position

Here’s some updates on my Spring schedule.

On March 19, I will be presenting the EMBARK program and what we aim to achieve at a conference organised by the Swedish Medical Products Agency called NordicMappingAMR. The event will feature an overview of existing monitoring of antibiotics and antibiotic resistant bacteria in the environment. The conference aims to present the results from this survey, to listen to experts in the field and to discuss possible progress. It takes place in Uppsala. For any further questions, contact Kia Salin at NordicMappingAMR@lakemedelsverket.se

Then on May 18 to 20 I will participate in the 7th Microbiome & Probiotics R&D and Business Collaboration Forum in Rotterdam. This industry/academia cross-over event focuses on cutting-edge microbiome and probiotics research, and challenges and opportunities in moving research towards commercialisation. I will talk on the work we do on deciphering genetic mechanisms behind microbial interactions in microbiomes on May 20.

And finally, I also want to bring the attention to that my collaborator Erik Kristiansson has an open PhD position in his lab. The position is funded by the Environmental Dimensions of Antibiotic Resistance (EDAR) research project, aiming to describe the environmental role in the development and promotion of antibiotic resistance. The focus of the PhD position will be on analysis of large-scale data, with special emphasis on the identification of new forms of resistance genes. The project also includes phylogenetic analysis and development of methods for assessment of gene evolution. More info can be found here.

Open postdoc position

We are hiring a postdoc to work with environmental monitoring of antimicrobial resistance. The project is part of the EMBARK program and will consider different aspects of establishing a baseline for background antibiotic resistance in the environment, standardization of monitoring protocols and development of methods to detect emerging resistance threats. The project will involve work with environmental sampling, DNA extractions, bacterial culturing and generation of large-scale DNA sequence data. In terms of bioinformatic analyses, the project will encompass analysis of next-generation sequence data, genome-resolved metagenomics, short-read assembly and network analysis.

We look for a skilled bioinformatician, preferably with experience of experimental laboratory work. If you feel that you are the right person for this position, you can apply here. More information is also available here. We look forward to your application! The deadline for applications is January 3.

EMBARK funded by JPIAMR

I am very happy to announce today (on the European Antibiotic Awareness Day), that the EMBARK project that I am coordinator for got funded by JPIAMR with almost 1.4 million Euros over three years!

The primary goal of EMBARK is to establish a baseline for how common resistance is in the environment and what resistance types that can be expected where. That background data will then underpin efforts to standardize different methods for resistance surveillance and identify high-priority targets that should be used for efficient monitoring. In addition, EMBARK will develop and evaluate methods to detect new resistance factors and thereby provide an early-warning system for emerging resistance threats.

EMBARK is an international collaboration funded by JPIAMR. The consortium consists of myself, Thomas Berendonk (TU-Dresden, Germany), Luis Pedro Coelho (Fudan University, China), Sofia Forslund (ECRC Max-Delbrück-Centrum für Molekulare Medizin, Germany), Etienne Ruppé (INSERM, France) and Rabaab Zahra (Quaid-i-Azam University, Pakistan).

EMBARK has a website where the protocols and data generated during the project will be released. Follow our progress towards better monitoring of antimicrobial resistance in the environment here and on the EMBARK Twitter account: @EMBARK_JPIAMR!