Yesterday, a paper I co-authored with my colleagues Chandan Pal, Erik Kristiansson and Joakim Larsson on the co-occurences of resistance genes against antibiotics, biocides and metals in bacterial genomes and plasmids became published in BMC Genomics. In this paper (1) we utilize the publicly available, fully sequenced, genomes and plasmids in GenBank to investigate the co-occurence network of resistance genes, to better understand risks for co-selection for resistance against different types of compounds. In short, the findings of the paper are that:
- ARGs are associated with BMRG-carrying bacteria and the co-selection potential of biocides and metals is specific towards certain antibiotics
- Clinically important genera host the largest numbers of ARGs and BMRGs and those also have the highest co-selection potential
- Bacteria isolated from human and domestic animal origins have the highest co-selection potential
- Plasmids with co-selection potential tend to be conjugative and carry toxin-antitoxin systems
- Mercury and QACs are potential co-selectors of ARGs on plasmids, however BMRGs are common on chromosomes and could still have indirect co-selection potential
- 14 percent of bacteria and more than 70% of the plasmids completely lacked resistance genes
This analysis was possible thanks to the BacMet database of antibacterial biocide and metal resistance genes, published about two years ago (2). The visualization of the plasmid co-occurence network we ended up with can be seen below. Note the strong connection between the mercury resistance mer operon and the antibiotic resistance genes to the right.
On a side note, it is interesting to note that the underrepresentation of detoxification systems in marine environments we noted last year (3) still seems to hold for genomes (and particularly plasmids), supporting the genome streamlining hypothesis (4).
- Pal C, Bengtsson-Palme J, Kristiansson E, Larsson DGJ: Co-occurrence of resistance genes to antibiotics, biocides and metals reveals novel insights into their co-selection potential. BMC Genomics, 16, 964 (2015). doi: 10.1186/s12864-015-2153-5 [Paper link]
- Pal C, Bengtsson-Palme J, Rensing C, Kristiansson E, Larsson DGJ: BacMet: Antibacterial Biocide and Metal Resistance Genes Database. Nucleic Acids Research, 42, D1, D737-D743 (2014). doi: 10.1093/nar/gkt1252 [Paper link]
- Bengtsson-Palme J, Alm Rosenblad M, Molin M, Blomberg A: Metagenomics reveals that detoxification systems are underrepresented in marine bacterial communities. BMC Genomics, 15, 749 (2014). doi: 10.1186/1471-2164-15-749 [Paper link]
- Giovannoni SJ, Cameron TJ, Temperton B: Implications of streamlining theory for microbial ecology. ISME Journal, 8, 1553-1565 (2014).
The paper we published in August on travelers carrying resistance genes with them in their gut microbiota has now been typeset and got proper volume and issue numbers assigned to it in Antimicrobial Agents and Chemotherapy. Take a look at it, I personally think it’s quite good-looking.
Also, if you understand Swedish, here is an interview with me broadcasted on Swedish Radio last month about this study and the consequences of it.
The new citation for the paper is:
- Bengtsson-Palme J, Angelin M, Huss M, Kjellqvist S, Kristiansson E, Palmgren H, Larsson DGJ, Johansson A: The human gut microbiome as a transporter of antibiotic resistance genes between continents. Antimicrobial Agents and Chemotherapy, 59, 10, 6551-6560 (2015). doi: 10.1128/AAC.00933-15 [Paper link]
Earlier today, my most recent paper (1) became available online, describing resistance gene patterns in the gut microbiota of Swedes before and after travel to the Indian peninsula and central Africa. In this work, we have used metagenomic sequencing of the intestinal microbiome of Swedish students returning from exchange programs to show that the abundance of antibiotic resistance genes in several classes are increased after travel. This work reiterates the findings of several papers describing uptake of resistant bacteria (2-8) or resistance genes (9-11) after travel to destinations with worse resistance situation.
Our paper is important because it:
- Addresses the abundance of a vast range of resistance genes (more than 300).
- Finds evidence for that the overall relative abundance of antibiotic resistance genes increased after travel, without any intake of antibiotics.
- Shows that the sensitivity of metagenomics was, despite very deep sequencing efforts, not sufficient to detect acquisition of the low-abundant (CTX-M) resistance genes responsible for observed ESBL phenotypes.
- Reveals a “core resistome” of resistance genes that are more or less omnipresent, and remain relatively stable regardless of travel, while changes seem to occur in the more variable part of the resistome.
- Hints at increased abundance of Proteobacteria after travel, although this increase could not specifically be linked to resistance gene increases.
- Uses de novo metagenomic assembly to physically link resistance genes in the same sample, giving hints of co-resistance patterns in the gut microbiome.
The paper was a collaboration with Martin Angelin, Helena Palmgren and Anders Johansson at Umeå University, and was made possible by bioinformatics support from SciLifeLab in Stockholm. I highly recommend reading it as a complement to e.g. the Forslund et al. paper (12) describing country-specific antibiotic resistance patterns in the gut microbiota.
Taken together, this study offers a broadened perspective on how the antibiotic resistance potential of the human gut microbiome changes after travel, providing an independent complement to previous studies targeting a limited number of bacterial species or antibiotic resistance genes. Understanding how resistance genes travels the globe is hugely important, since resistance in principle only need to appear in a pathogen once; improper hygiene and travel may then spread novel resistance genes across continents rapidly (13,14).
- Bengtsson-Palme J, Angelin M, Huss M, Kjellqvist S, Kristiansson E, Palmgren H, Larsson DGJ, Johansson A: The human gut microbiome as a transporter of antibiotic resistance genes between continents. Antimicrob Agents Chemother Accepted manuscript posted online (2015). doi: 10.1128/AAC.00933-15 [Paper link]
- Gaarslev K, Stenderup J: Changes during travel in the composition and antibiotic resistance pattern of the intestinal Enterobacteriaceae flora: results from a study of mecillinam prophylaxis against travellers’ diarrhoea. Curr Med Res Opin 9:384–387 (1985).
- Paltansing S, Vlot JA, Kraakman MEM, Mesman R, Bruijning ML, Bernards AT, Visser LG, Veldkamp KE: Extended-spectrum β-lactamase-producing enterobacteriaceae among travelers from the Netherlands. Emerging Infect. Dis. 19:1206–1213 (2013).
- Ruppé E, Armand-Lefèvre L, Estellat C, El-Mniai A, Boussadia Y, Consigny PH, Girard PM, Vittecoq D, Bouchaud O, Pialoux G, Esposito-Farèse M, Coignard B, Lucet JC, Andremont A, Matheron S: Acquisition of carbapenemase-producing Enterobacteriaceae by healthy travellers to India, France, February 2012 to March 2013. Euro Surveill. 19 (2014).
- Kennedy K, Collignon P: Colonisation with Escherichia coli resistant to “critically important” antibiotics: a high risk for international travellers. Eur J Clin Microbiol Infect Dis 29:1501–1506 (2010).
- Tham J, Odenholt I, Walder M, Brolund A, Ahl J, Melander E: Extended-spectrum beta-lactamase-producing Escherichia coli in patients with travellers’ diarrhoea. Scand. J. Infect. Dis. 42:275–280 (2010).
- Östholm-Balkhed Å, Tärnberg M, Nilsson M, Nilsson LE, Hanberger H, Hällgren A, Travel Study Group of Southeast Sweden: Travel-associated faecal colonization with ESBL-producing Enterobacteriaceae: incidence and risk factors. J Antimicrob Chemother 68:2144–2153 (2013).
- Kantele A, Lääveri T, Mero S, Vilkman K, Pakkanen SH, Ollgren J, Antikainen J, Kirveskari J: Antimicrobials increase travelers’ risk of colonization by extended-spectrum betalactamase-producing enterobacteriaceae. Clin Infect Dis 60:837–846 (2015).
- von Wintersdorff CJH, Penders J, Stobberingh EE, Oude Lashof AML, Hoebe CJPA, Savelkoul PHM, Wolffs PFG: High rates of antimicrobial drug resistance gene acquisition after international travel, The Netherlands. Emerging Infect. Dis. 20:649–657 (2014).
- Tängdén T, Cars O, Melhus A, Löwdin E: Foreign travel is a major risk factor for colonization with Escherichia coli producing CTX-M-type extended-spectrum beta-lactamases: a prospective study with Swedish volunteers. Antimicrob Agents Chemother 54:3564–3568 (2010).
- Dhanji H, Patel R, Wall R, Doumith M, Patel B, Hope R, Livermore DM, Woodford N: Variation in the genetic environments of bla(CTX-M-15) in Escherichia coli from the faeces of travellers returning to the United Kingdom. J Antimicrob Chemother 66:1005–1012 (2011).
- Forslund K, Sunagawa S, Kultima JR, Mende DR, Arumugam M, Typas A, Bork P: Country-specific antibiotic use practices impact the human gut resistome. Genome Res 23:1163–1169 (2013).
- Bengtsson-Palme J, Larsson DGJ: Antibiotic resistance genes in the environment: prioritizing risks. Nat Rev Microbiol 13:396 (2015).
- Larsson DGJ: Antibiotics in the environment. Ups J Med Sci 119:108–112 (2014).
If you’re looking for super-interesting jobs within bioinformatics, you don’t need to look any further. Instead, you should apply for a position at 1928 Diagnostics here in Gothenburg and join them in the fight against antibiotic resistant bacteria. The position is in the development team and the deadline for application is December 19. All the details can be found here.
The first work in which I have employed metagenomics to investigate antibiotic resistance has been accepted in Frontiers in Microbiology, and is (at the time of writing) available as a provisional PDF. In the paper (1), which is co-authored by Fredrik Boulund, Jerker Fick, Erik Kristiansson and Joakim Larsson, we have used shotgun metagenomic sequencing of an Indian lake polluted by dumping of waste from pharmaceutical production. We used this data to describe the diversity of antibiotic resistance genes and the genetic context of those, to try to predict their genetic transferability. We found resistance genes against essentially every major class of antibiotics, as well as large abundances of genes responsible for mobilization of genetic material. Resistance genes were estimated to be 7000 times more abundant in the polluted lake than in a Swedish lake included for comparison, where only eight resistance genes were found. The abundances of resistance genes have previously only been matched by river sediment subject to pollution from pharmaceutical production (2). In addition, we describe twenty-six known and twenty-one putative novel plasmids from the Indian lake metagenome, indicating that there is a large potential for horizontal gene transfer through conjugation. Based on the wide range and high abundance of known resistance factors detected, we believe that it is plausible that novel resistance genes are also present in the lake. We conclude that environments polluted with waste from antibiotic manufacturing could be important reservoirs for mobile antibiotic resistance genes. This work further highlights previous findings that pharmaceutical production settings could provide sufficient selection pressure from antibiotics (3) to drive the development of multi-resistant bacteria (4,5), resistance which may ultimately end up in pathogenic species (6,7). The paper can be read in its entirety here.
- Bengtsson-Palme J, Boulund F, Fick J, Kristiansson E, Larsson DGJ: Shotgun metagenomics reveals a wide array of antibiotic resistance genes and mobile elements in a polluted lake in India. Frontiers in Microbiology, Volume 5, Issue 648 (2014). doi: 10.3389/fmicb.2014.00648
- Kristiansson E, Fick J, Janzon A, Grabic R, Rutgersson C, Weijdegård B, Söderström H, Larsson DGJ: Pyrosequencing of antibiotic-contaminated river sediments reveals high levels of resistance and gene transfer elements. PLoS ONE, Volume 6, e17038 (2011). doi:10.1371/journal.pone.0017038.
- Larsson DGJ, de Pedro C, Paxeus N: Effluent from drug manufactures contains extremely high levels of pharmaceuticals. J Hazard Mater, Volume 148, 751–755 (2007). doi:10.1016/j.jhazmat.2007.07.008
- Marathe NP, Regina VR, Walujkar SA, Charan SS, Moore ERB, Larsson DGJ, Shouche YS: A Treatment Plant Receiving Waste Water from Multiple Bulk Drug Manufacturers Is a Reservoir for Highly Multi-Drug Resistant Integron-Bearing Bacteria. PLoS ONE, Volume 8, e77310 (2013). doi:10.1371/journal.pone.0077310
- Johnning A, Moore ERB, Svensson-Stadler L, Shouche YS, Larsson DGJ, Kristiansson E: Acquired genetic mechanisms of a multiresistant bacterium isolated from a treatment plant receiving wastewater from antibiotic production. Appl Environ Microbiol, Volume 79, 7256–7263 (2013). doi:10.1128/AEM.02141-13
- Pruden A, Larsson DGJ, Amézquita A, Collignon P, Brandt KK, Graham DW, Lazorchak JM, Suzuki S, Silley P, Snape JR., et al.: Management options for reducing the release of antibiotics and antibiotic resistance genes to the environment. Environ Health Perspect, Volume 121, 878–885 (2013). doi:10.1289/ehp.1206446
- Finley RL, Collignon P, Larsson DGJ, McEwen SA, Li X-Z, Gaze WH, Reid-Smith R, Timinouni M, Graham DW, Topp E: The scourge of antibiotic resistance: the important role of the environment. Clin Infect Dis, Volume 57, 704–710 (2013). doi:10.1093/cid/cit355
If you are thinking about doing a PhD and think that bioinformatics and antibiotic resistance is a cool subject, then now is your chance to come and join us for the next four years! There is a PhD position open i Joakim Larsson’s group, which means that if you get the job you will work with me, Joakim Larsson, Erik Kristiansson, Ørjan Samuelsen and Carl-Fredrik Flach on a super-interesting project relating to discovery of novel beta-lactamase genes (NoCURE). The project aims to better understand where, how and under what circumstances these genetic transfer events take place, in order to provide opportunities to limit or delay resistance development and thus increase the functional lifespan of precious antibiotics. The lion’s share of the work will be related to interpreting large-scale sequencing data generated by collaborators within the project; both genome sequencing and metagenomic data.
This is a great opportunity to prove your bioinformatics skills and use them for something urgently important. Full details about the position can be found here.
If you’re looking for a PhD position in bioinformatics, working with antibiotic resistance, there’s an opening in Erik Krisiansson’s (best bioinformatician in Gothenburg? I think so) group. To apply you need to have a master’s level degree in bioinformatics, mathematical statistics, mathematics, computer science, physics, molecular biology or any equivalent topic, obtained latest June 2014. If you’re a master student and want to join us, this is your chance! You can read more and apply for the position here.