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:
- 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.
- 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.
- 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!
- 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]
- 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
- 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]
I am a bit late on the ball here, but January was a great month for the lab in terms of funding. First, we got awarded an Sahlgrenska Academy International Starting Grant – a faculty grant for young researchers comprising of 1 million SEK, intended to support the overall research plan for the lab.
The second grant was awarded by the Centre for Antibiotic Resistance Research (CARe) at the University of Gothenburg and is a project grant focusing on opportunistic pathogens and their role in the emergence and transmission of antibiotic resistance. For this project, we got almost 600,000 SEK over two years to investigate how genes enhancing invasion ability and virulence interact with selection for antibiotic resistance in opportunistic pathogens. The project is somewhat related to the work I did in Prof. Jo Handelsman‘s lab, but extends it to more mechanistic details about how these phenomena are interconnected.
The outcomes from a workshop arranged by JPIAMR, the Swedish Research Council (VR) and CARe were just published as a short review paper in Environment International. In the paper, which was mostly moved forward by Prof. Joakim Larsson at CARe, we describe four major areas of knowledge gaps in the realm of environmental antibiotic resistance (1). We then highlight several important sub-questions within these areas. The broad areas we define are:
- What are the relative contributions of different sources of antibiotics and antibiotic resistant bacteria into the environment?
- What is the role of the environment as affected by anthropogenic inputs (e.g. pollution and other activities) on the evolution (mobilization, selection, transfer, persistence etc.) of antibiotic resistance?
- How significant is the exposure of humans to antibiotic resistant bacteria via different environmental routes, and what is the impact on human health?
- What technological, social, economic and behavioral interventions are effective to mitigate the emergence and spread of antibiotic resistance via the environment?
Although much has been written on the topic before (e.g. 2-12), I think it is unique that we collect and explicitly point out areas in which we are lacking important knowledge to build accurate risk models and devise appropriate intervention strategies. The workshop was held in Gothenburg on the 27–28th of September 2017. The workshop leaders Joakim Larsson, Ana-Maria de Roda Husman and Ramanan Laxminarayan were each responsible for moderating a breakout group, and every breakout group was tasked to deal with knowledge gaps related to either evolution, transmission or interventions. The reports of the breakout groups were then discussed among all participants to clarify and structure the areas where more research is needed, which boiled down to the four overarching critical knowledge gaps described in the paper (1).
This is a short paper, and I think everyone with an interest in environmental antibiotic resistance should read it and reflect over its content (because, we may of course have overlooked some important aspect). You can find the paper here.
- Larsson DGJ, Andremont A, Bengtsson-Palme J, Brandt KK, de Roda Husman AM, Fagerstedt P, Fick J, Flach C-F, Gaze WH, Kuroda M, Kvint K, Laxminarayan R, Manaia CM, Nielsen KM, Ploy M-C, Segovia C, Simonet P, Smalla K, Snape J, Topp E, van Hengel A, Verner-Jeffreys DW, Virta MPJ, Wellington EM, Wernersson A-S: Critical knowledge gaps and research needs related to the environmental dimensions of antibiotic resistance. Environment International, 117, 132–138 (2018). doi: 10.1016/j.envint.2018.04.041
- 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
- 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
- Bengtsson-Palme J, Larsson DGJ: Antibiotic resistance genes in the environment: prioritizing risks. Nature Reviews Microbiology, 13, 369 (2015). doi: 10.1038/nrmicro3399-c1
- Ashbolt NJ, Amézquita A, Backhaus T, Borriello P, Brandt KK, Collignon P, et al.: Human Health Risk Assessment (HHRA) for Environmental Development and Transfer of Antibiotic Resistance. Environmental Health Perspectives, 121, 993–1001 (2013)
- Pruden A, Larsson DGJ, Amézquita A, Collignon P, Brandt KK, Graham DW, et al.: Management options for reducing the release of antibiotics and antibiotic resistance genes to the environment. Environmental Health Perspectives, 121, 878–85 (2013).
- Gillings MR: Evolutionary consequences of antibiotic use for the resistome, mobilome and microbial pangenome. Frontiers in Microbiology, 4, 4 (2013).
- Baquero F, Alvarez-Ortega C, Martinez JL: Ecology and evolution of antibiotic resistance. Environmental Microbiology Reports, 1, 469–476 (2009).
- Baquero F, Tedim AP, Coque TM: Antibiotic resistance shaping multi-level population biology of bacteria. Frontiers in Microbiology, 4, 15 (2013).
- Berendonk TU, Manaia CM, Merlin C et al.: Tackling antibiotic resistance: the environmental framework. Nature Reviews Microbiology, 13, 310–317 (2015).
- Hiltunen T, Virta M, Laine A-L: Antibiotic resistance in the wild: an eco-evolutionary perspective. Philosophical Transactions of the Royal Society B: Biological Sciences, 372 (2017) doi: 10.1098/rstb.2016.0039.
- Martinez JL: Bottlenecks in the transferability of antibiotic resistance from natural ecosystems to human bacterial pathogens. Frontiers in Microbiology, 2, 265 (2011).
So 2017 has begun, and this year will bring new challenges and exciting opportunities. First of all, my application for a 3.5 year grant from the Swedish Research Council for Environment, Agricultural Sciences and Spatial Planning (FORMAS) to go to Prof. Jo Handelsman‘s lab in the US was granted. Since Prof. Handelsman in is moving her lab to University of Wisconsin in Madison, where she will be heading the Wisconsin Institute of Discovery (after returning from the White House), it means that this summer I will be moving to Wisconsin. I will retain a link to the University of Gothenburg and the Joakim Larsson lab though, and part of the grant is actually for covering my salary after returning from the US, so Gothenburg won’t get rid of me so easily.
The granted project will use high-throughput sequencing techniques to identify genes improving colonization and invasion ability or resistance to invasion in microbial communities, using a model system developed by the Handelsman lab. The project will focus on genes important for colonization, invasion and resistance to invasion under exposure to sub-lethal antibiotics concentrations. The project will contribute important knowledge towards the understanding of microbial colonization and invasion and highlight disturbances to the interactions in microbial communities caused by anthropogenic activities. In addition, the results of the project will hopefully allow for prediction of secondary effects of antibiotic exposure in the environment, and the preparation for future challenges related to infections with pathogenic bacteria. The project has already been highlighted by CARe (although this was before Jo announced her move from Yale) and a FORMAS press release (in Swedish).
The project will go under the acronym InSiDER, and I intend to write about it in a special section of the website, called the Wisconsin Blog. My intention is to include personal reflections on life in Wisconsin and work in the Handelsman lab there, but we’ll see how those plans turn out. Anyway, I am very thankful for FORMAS funding this project and giving me the opportunity to work with one of the leading scientists within microbial ecology in the world!