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Daniel Rozen
leiden university
institute of biology

Antibiotic resistance among the killers


Author(s): Rozen, DE, Grimbergen, A


The discovery and development of antibiotics as part of the medical arsenal is one of the great triumphs in the effort to eradicate bacterial diseases. For more than 70 years these microbial products have worked with remarkable success, transforming the medical landscape and dramatically improving human health. However, despite their tremendous relevance for humans, there is a surprising lack of understanding of the role of antibiotics in nature for the organisms that produce them. Why are antibiotics produced and why do strains in nature evolve to resist them. Here we test the idea that antibiotic-mediated interference competition between coexisting bacterial species in soil drives reciprocal coevolutionary changes as strains evolve novel mechanisms of killing and resistance. Focusing on the prolific antibiotic producing genus, Streptomyces, and their coexisting competitors, we first characterize interaction networks between coexisting Streptomycetes and then ask whether antibiotic resistance shows evidence of local adaptation. Second, we are investigating the costs and in situ fitness of naturally resistant strains of Streptomyces in soil at different antibiotic concentrations and during co-cultivation with Streptomycetes that are natural antibiotic producers. Our work examines the natural context and population dynamics of resistance evolution, thereby providing insight into processes occurring in the clinical environment.

Ana Sousa
Instituto Gulbenkian de Ciencia

Antibiotic resistance and stress in the light of Fisher’s model


Author(s): Sousa, A, Trindade, S, Gordo, I


The role of mutations in evolution depends upon the distribution of their effects on fitness. This distribution is likely to depend on the environment. Indeed genotype-by-environment interactions are key for the process of local adaptation and ecological specialization. An important trait in bacterial evolution is antibiotic resistance, which presents a clear case of change in the direction of selection between environments with and without antibiotics. Here, we study the distribution of fitness effects of mutations, conferring antibiotic resistance to Escherichia coli, in benign and stressful environments without drugs.We interpret the distributions in the light of a fitness landscape model that assumes a single fitness peak. We find that mutation effects (s) arewell described by a shifted gamma distribution, with a shift parameter that reflects the distance to the fitness peak and varies across environments. Consistent with the theoretical predictions of Fisher’s geometrical model, with a Gaussian relationship between phenotype and fitness, we find that the main effect of stress is to increase the variance in s. Our findings are in agreement with the results of a recent meta-analysis, which suggest that a simple fitness landscape model may capture the variation of mutation effects across species and environments.

Matti Jalasvuori
University of Jyväskylä
Department of Biological and Environmental Science

Deadly antibiotics and evolutionary rescue via horizontal gene transfer


Author(s): Jalasvuori, M, Ojala, V, Mattila, S


Evolution has caused one of the most concrete problems in the modern world by selecting for drug resistant bacteria. When bacteria are exposed to lethal levels of antibiotics, it has been assumed that there needs to be a pre-existing mutation for resistance within the population in order for the bacterial strain to survive the drug treatment. However and given that majority of resistance genes are carried by mobile genetic elements such as conjugative plasmids that can move between bacterial cells, it is possible that the resistance gene pre-exist in another bacterium which then rescues susceptible bacteria via horizontal gene transfer. We investigated whether bacteria may survive lethal antibiotic selection by acquiring resistance genes horizontally, and, if so, could this process be somehow prevented. Indeed and contradictory to previous paradigm, we demonstrate that the resistance does not need to pre-exist within the population as some bacteriosidic antibiotics cannot kill susceptible bacteria when the surrounding bacterial community carries mobile elements with resistance genes. Moreover, we show that viruses specifically infecting bacteria with mobile elements can both prevent the spread of resistances to other bacteria and to lead to the loss of resistance conferring elements from the population. Altogether these results suggest that the composition of bacterial community along with their viruses can play a defining role in the evolution antibiotic resistances.

Clara Torres-Barceló
University of Oxford
Department of Zoology
United Kingdom

Direct benefit of the SOS response vanishes after long term evolution in P. aeruginosa


Author(s): Torres-Barceló, C, Moxon, R, McWilliam, M, MacLean, R


Exposure to stressors, such as antibiotics, induces the expression of response pathways that could provide bacteria with a direct fitness benefit, stemming from increased protection against stress, and an indirect fitness benefit, stemming from increased evolvability due to elevated mutagenesis. We have quite a good understanding of the molecular mechanisms of stress response pathways, but quantitative measurements of the direct and indirect fitness benefits and costs associated with stress response pathway expression are lacking. By measuring the competitive fitness of wildtype and LexA mutant (SOS response blocked) strains of P. aeruginosa we show that the SOS response provides with a direct benefit across a range of sub-lethal concentrations of the antibiotic ciprofloxacin. Interestingly, in the absence of the antibiotic, the LexA mutation confers an advantage in the competitive ability and demonstrates the existence of a cost for the cells owning this complex pathway. We also analyse important parameters like cell viability, cell size and growth rate to explain the higher fitness of wildtype during selection with antibiotic. However, we find that the SOS pathway produces no indirect fitness benefit, as demonstrated by the fact that the LexA mutant shows a comparable ability to adapt to ciprofloxacin over a 600 generation selection experiment. Our study clearly demonstrates that natural selection favours the evolution of stress-induced mutagenesis pathways as a result of direct selection for increased stress tolerance and not indirect selection to favour evolvability. Altogether, we contribute with experimental evidence crucial to disentangle if bacterial stress responses play a role in accelerating adaptation to stressors such as antibiotics.

Alex Hall
ETH Zürich
Institute of Integrative Biology

Effect of Phages on the Cost of Antibiotic Resistance


Author(s): Hall, A, Angst, D


Experimental studies of antibiotic resistance evolution typically employ a single bacterial species in pure culture. However, outside the laboratory, parasitism of bacteria by viruses (phages) is ubiquitous. I used experimental populations of Escherichia coli to show that phage parasitism altered the outcomes of competitions between antibiotic-resistant and sensitive genotypes. Phages caused rapid selective sweeps, associated with the emergence of phage-resistant mutants, and this was approximately equally likely to favour antibiotic-resistant or sensitive genotypes when their initial frequencies were similar. An elevated mutation rate was advantageous in the presence of phages, suggesting that a given antibiotic-resistant or sensitive genotype is more likely to fix under phage parasitism when it has a high mutation supply rate relative to other genotypes. Given their abundance in nature, phages probably modify selection on other traits in many different scenarios.

Jeremy Dettman
University of Ottawa

Evolutionary genomics of epidemic and non-epidemic strains of Pseudomonas aeruginosa


Author(s): Dettman, JR, Rodrigue, N, Kassen, R


Pseudomonas aeruginosa is an opportunistic pathogen of humans and is the most common bacterial species isolated from the respiratory tracts of adult patients with cystic fibrosis (CF). Chronic infection of the CF lung can lead to decades of direct interaction between the host and resident P. aeruginosa population. Longitudinal studies have documented the patterns of adaptation to the CF lung, and evidence to date suggests that a large number of genes are targets for mutation, but most are mutated in only a small fraction of infections. A more comprehensive view therefore requires the comparison of a larger sample of diverse clinical isolates. To this end, we obtained whole genome sequence data from a collection of P. aeruginosa isolated from the airways of CF patients in order to investigate general patterns of adaptation associated with chronic infection. We also focus attention on a transmissible, epidemic strain that was recently reported within North America. We present multiple lines of evidence that the history of selection imposed by the CF lung environment has a major influence on genomic evolution and the genetic characteristics of isolates causing contemporary infection. We identify candidate genes and important functional pathways, and find that the presence of oxidative stressors and antibiotics appear to be key factors that have driven the adaptive evolution of this pathogen within the host.

Arjan DeVisser
Wageningen University

Exploring the evolvability of an antibiotic resistance enzyme


Author(s): DeVisser, A, Schenk, M, Salverda, M, Szendro, I, Krug, J


For a quantitative understanding of the process of adaptation, we need to understand its ‘raw material’, that is the properties of beneficial mutations. In my talk, I will focus on two properties in particular, the frequency distribution of fitness effects of beneficial mutations and their epistatic interactions, and how these determine the pathway and outcome of evolution. In the experiments that I will present, we study the in vitro evolution of the enzyme TEM-1 beta-lactamase, a notorious determinant of antibiotic resistance in bacteria. The first two studies are systematic investigations of the short-term evolvability of the enzyme, including the number and effects of beneficial mutations and their epistatic interactions. The last two studies address the role of the structure of the fitness landscape (caused by epistasis) and population size on long-term evolvability. Surprisingly, we find that small populations sometimes reach higher resistance than large populations, showing the important role of chance events for long-term adaptation.

Adin Ross-Gillespie
University of Zurich
Institute of Plant Biology

Extracellular quenching of bacterial public goods as an ‘evolution-proof’ anti-virulence therapy: a case study with Pseudomonas aeruginosa


Author(s): Ross-Gillespie, A, Weigert, M, Weigert, M, Brown, SP, Kümmerli, R, Kümmerli, R


Many bacterial exoproducts yield population-level benefits. Such ‘public goods’ (PG) include key virulence factors, and therapies designed to block their production are attracting increasing attention nowadays. The disruption of cell-to-cell communication (quorum sensing, QS), is considered especially promising because it could block production of multiple exoproducts, yet should prompt weaker selection for resistance than conventional antimicrobials. However, initial enthusiasm for this approach (‘quorum quenching’, QQ) has been tempered by claims that resistance in fact evolves readily, for example by improving pumps to eject QQ compounds from cells. Here, we focus on a different strategy, in which PGs (siderophores) are quenched outside producer cells. We show that adding gallium (Ga) to iron-limited Pseudomonas aeruginosa cultures suppresses growth in a dose-dependent manner by (a) deactivating siderophores and thereby choking the supply of iron, and (b) inducing costly production of further siderophores. In experimental infections of moth larvae (Galleria mellonella), Ga suppressed bacterial growth and extended larval survival. Crucially, moderate levels of Ga reduced virulence below those of infections with siderophore-defective mutant strains, which suggests that Ga also induces siderophore overproduction in vivo, imposing extra metabolic burden on bacteria without generating benefits. We argue that strategies that quenching secreted PGs extracellularly should be more effective than those that inhibit synthesis in the cell, since PG production costs remain or even increase. With Ga-mediated PG-quenching, resistance is particularly unlikely to evolve because (a) extracellular quenching is impervious to typical within-cell resistance traits; (b) avoiding siderophore production is maladaptive (non-producing ‘cheats’ could not spread in our experiments); and (c) evolving siderophores with reduced susceptibility to Ga appears to be biochemically unfeasible.

Samuel Tazzyman
Institute of Integrative Biology at ETH Zürich

Modelling antibiotic resistance and plasmids


Author(s): Tazzyman, SJ


The spread of antibiotic resistance in bacteria is a major public health problem, threatening our ability to treat bacterial infections successfully.

Plasmids, extra-chromosomal pieces of DNA capable of horizontal transfer, are often implicated in the process of resistance acquisition, and potentially allow for the transfer of resistance genes between species and between genera. Some plasmids carry multiple resistance genes, simultaneously counteracting several antibiotics, and in extreme cases acquisition of a plasmid by a pathogen can confer resistance to virtually all antibiotics at a single stroke. The conditions favouring resistance genes to be located on plasmids rather than on chromosomes are therefore potentially of great importance.

Mathematical models are an excellent technique for investigating this topic, because they allow for simultaneous consideration of selection at three levels: genes, plasmids, and bacteria. We use models to consider whether plasmids are a favourable location for antibiotic resistance genes, and how spatially- or temporally-varying selection regimes can affect this. Answers to these questions provide a more complete understanding of the processes underlying the evolution of antibiotic resistance genes on plasmids, and could consequently be of great value in preventing the spread of resistance.

Stéphanie Bedhomme

Multilevel evolutionary changes after horizontal gene transfer of an antibiotic resistance gene


Author(s): Bedhomme, S, Amorós-Moya, D, Pujana, M, Valero, L, Bravo, IG


Horizontal gene transfer is a powerful mechanism by which antibiotic resistance spread among species. However, the maintenance of a horizontally transferred antibiotic resistance gene is not granted, because of its low level of adaptation to the receiving organism. In particular, transferred genes usually have codon preferences that differ from the ones of the receiving genome. This leads to translation errors, low translation rates and finally to low activity of the transferred gene and energetic costs for the receiving cell. It is theoretically predicted that a deoptimized codon usage gene will undergo an amelioration process - i.e. its sequence will evolve towards a codon usage similar to the host one - and a fine tuning of its expression and of the expression of interacting genes. To test these predictions, three synonymous versions of the Chloramphenicol Acetyl Transferase with different codon preferences were designed and transfected in Escherichia coli. After verifying that unadapted codon usage induced a fitness cost, we experimentally evolved these populations for 1000 generations. At the phenotypic level, the cost of codon usage deadaptation was totally compensated. However, at the genotypic level, no amelioration process was observed but various genetic changes occurred ranging from mutations in the promoter to gene loss to plasmid copy number reduction and to genetic changes in the bacteria chromosome. At the proteome level, the presence of a codon usage biased gene and the posterior evolution affected the expression of a high number of proteins. Our results suggest that the presence of horizontally transferred gene with a different codon usage induces selection pressures leading to a refactorization of the bacterial functioning. Horizontal transfer of antibiotic resistance gene thus reveals itself, not only as a spreading highway for these genes but also as a powerful mechanism pushing bacteria to explore new ways of functioning.


Chairman: Octávio S. Paulo
Tel: 00 351 217500614 direct
Tel: 00 351 217500000 ext22359
Fax: 00 351 217500028


XIV Congress of the European Society for Evolutionary Biology

Organization Team
Department of Animal Biology (DBA)
Faculty of Sciences of the University of Lisbon
P-1749-016 Lisbon


Computational Biology & Population Genomics Group