Category: EMBARK

What is the latent resistome? This is a term we coin in a new paper published yesterday in Microbiome. In the paper, we distinguish between the small number antibiotic resistance genes (ARGs) that are established, well-characterized, and available in existing resistance gene databases (what we refer to as “established ARGs”). These are typically ARGs encountered in clinical pathogens and are often already causing problems in human and animal infections. The remaining latently present ARGs, which we denote “latent ARGs”, are less or not at all studied, and are therefore much harder to detect (1). These latent ARGs are typically unknown and generally overlooked in most studies of resistance. They are also seldom accounted for in risk assessments of antibiotic resistance (2-4). This means that our view of the resistome and its diversity is incomplete, which hampers our ability to assess risk for promotion and spread of yet undiscovered resistance determinants.

In our new study, we try to alleviate this issue by analyzing more than 10,000 metagenomic samples. We show that the latent ARGs are more abundant and diverse than established ARGs in all studied environments, including the human- and animal-associated microbiomes. The total pan-resistomes, i.e., all ARGs present in an environment (including the latent ARGs), are heavily dominated by these latent ARGs. In contrast, the core resistome (the ARGs that are commonly encountered) comprise both latent and established ARGs.

In the study, we identified several latent ARGs that were shared between environments or that are already present in human pathogens. These are often located on mobile genetic elements that can be transferred between bacteria. Finally, we also show that wastewater microbiomes have surprisingly large pan- and core-resistomes, which makes this environment a potent high-risk environment for mobilization and promotion of latent ARGs, which may make it into pathogens in the future.

It is also interesting to note that this new study echoes the results of my own study from 2018, showing that soil and water environments contain a high diversity of latent ARGs (or ARGs not found in pathogens as I put it in the 2018 study), despite being almost devoid of established ARGs (5).

This project has been a collaboration with Erik Kristiansson’s research group, and particularly with Juan Inda-Diáz. It has been great fun to work with them and I hope that we will keep this collaboration going into the future! The study can be read in its entirety here.

References

1. Inda-Díaz JS, Lund D, Parras-Moltó M, Johnning A, Bengtsson-Palme J, Kristiansson E: Latent antibiotic resistance genes are abundant, diverse, and mobile in human, animal, and environmental microbiomes. Microbiome, 11, 44 (2023). doi: 10.1186/s40168-023-01479-0 [Paper link]
2. Martinez JL, Coque TM, Baquero F: What is a resistance gene? Ranking risk in resistomes. Nature Reviews Microbiology 2015, 13:116–123. doi:10.1038/nrmicro3399
3. Bengtsson-Palme J, Larsson DGJ: Antibiotic resistance genes in the environment: prioritizing risks. Nature Reviews Microbiology, 13, 369 (2015). doi: 10.1038/nrmicro3399-c1
4. Bengtsson-Palme J: Assessment and management of risks associated with antibiotic resistance in the environment. In: Roig B, Weiss K, Thoreau V (Eds.) Management of Emerging Public Health Issues and Risks: Multidisciplinary Approaches to the Changing Environment, 243–263. Elsevier, UK (2019). doi: 10.1016/B978-0-12-813290-6.00010-X
5. Bengtsson-Palme J: The diversity of uncharacterized antibiotic resistance genes can be predicted from known gene variants – but not always. Microbiome, 6, 125 (2018). doi: 10.1186/s40168-018-0508-2

UNEP last week published their report on one health responses to antimicrobial resistance (1), which I have taken part in writing (well, I think I ultimately only contributed a few sentences here and there, but apparently that counts to be listed among the report’s contributors). The report, named “Bracing for Superbugs: Strengthening environmental action in the One Health response to antimicrobial resistance” showcases the evidence for that the environment plays a key role in the development, transmission and spread of AMR.

The report tries to unpack the different aspects of environmental AMR, and offers a fairly comprehensive picture of where the science stands on the subject. We also conclude that a systems effort – “One Health” – recognizing that the health of people, animals, plants and the environment are closely connected, is needed to tackle AMR.

This report analyzes the three economic sectors and their value chains that are key drivers of AMR development and spread in the environment: pharmaceuticals and other chemicals, agriculture including the food chain, and healthcare, together with pollutants from poor sanitation, sewage and waste effluent in municipal systems.

I am very happy to have been part of this report writing team and I hope that this will spur future action on AMR from a one-health perspective. You can read the entire report here.

Reference

1. United Nations Environment Programme (2023). Bracing for Superbugs: Strengthening environmental action in the One Health response to antimicrobial resistance. Geneva

I am very happy to share with you that our two doctoral students funded by the Wallenberg DDLS initiative have now started. One of them – Marcus Wenne – is already a well-known figure in the lab, as he has been with us as a master student and then as a bioinformatician for more than a year. The other student – Vi Varga – is a completely new face in the lab and just started yesterday.

Marcus will work in a project on global environmental AMR. He will also continue on his work on large-scale metagenomics to understand community dynamics and antibiotic resistance selection in microbial communities subjected to antibiotics selection. Marcus will work very closely to EMBARK and continue the important work we have done in that project over the next four years.

Vi will study responses of microbial communities to change, with a particular focus on comparative genomics and transcriptional approaches. We will link this to both community stability, pathogenesis and resistance to antibiotics, so this project involves a little bit of everything in terms of the lab’s research interests. Vi’s background is in comparative genomics and pathogenesis, so this seems to be the perfect mix to be able to carry out this project successfully!

Very welcome to the lab Marcus and Vi! We look forward to work with you for the next four years or so!

It’s been a busy couple of days at the DDLS Annual Meeting, so I did not have the time to post about this exciting news yesterday, but it is very exciting nonetheless.

I have been selected by the board of the Royal Swedish Academy of Sciences as the 2022 recipient of the Einhorn SIGHT award. The award recognizes outstanding global health research work by young researchers in the context of low- and middle-income countries, and specifically I have been selected thanks to my “outstanding research and development of tools to limit the global challenge of infectious diseases and antibiotic resistance.”

In a global health context, what is particularly important in the coming years is improved access to clean water and sewage systems. In addition, we also need to develop data-driven systems that can be used to implement easy-to-handle, inexpensive early warning systems and risk models for antibiotic-resistant bacteria, which we hope will be the outcome of the EMBARK program.

Clearly, a large part of this is the result of the work the entire EMBARK team has put together in the past couple of years. Another big part has been the work I have done together with Joakim Larsson in the area of antibiotic resistance in the environment. I am deeply grateful both to Joakim and my EMBARK collaborators for their contributions towards this award. Science is a teamwork, and it is a bit of a pity that we celebrate individuals to the extent we do (even though the recognition of my contribution of course is nice for me personally). Thanks to everyone who have been involved over the years!

There will be an award ceremony at the Royal Academy of Sciences on November 22, as part of a very nice event on Global Health, with the theme ‘Food Safety in conflict’. You can read a short interview I did in relation to the award here.

In other notes, I was also selected as one of Clarivate as one of this year’s Highly Cited Researchers (for the third year in a row!) This is of course also exciting news, although the most important aspect of that is that it shows that the research we do is useful to others!

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]

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).

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.

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.

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.

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!