Publications by authors named "Martin Ackermann"

95 Publications

Microfluidics for Single-Cell Study of Antibiotic Tolerance and Persistence Induced by Nutrient Limitation.

Methods Mol Biol 2021 ;2357:107-124

Department of Environmental Systems Science, Institute of Biogeochemistry and Pollutant Dynamics, ETH Zurich, Zurich, Switzerland.

Nutrient limitation is one of the most common triggers of antibiotic tolerance and persistence. Here, we present two microfluidic setups to study how spatial and temporal variation in nutrient availability lead to increased survival of bacteria to antibiotics. The first setup is designed to mimic the growth dynamics of bacteria in spatially structured populations (e.g., biofilms) and can be used to study how spatial gradients in nutrient availability, created by the collective metabolic activity of a population, increase antibiotic tolerance. The second setup captures the dynamics of feast-and-famine cycles that bacteria recurrently encounter in nature, and can be used to study how phenotypic heterogeneity in growth resumption after starvation increases survival of clonal bacterial populations. In both setups, the growth rates and metabolic activity of bacteria can be measured at the single-cell level. This is useful to build a mechanistic understanding of how spatiotemporal variation in nutrient availability triggers bacteria to enter phenotypic states that increase their tolerance to antibiotics.
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http://dx.doi.org/10.1007/978-1-0716-1621-5_8DOI Listing
January 2022

Quantification of the spread of SARS-CoV-2 variant B.1.1.7 in Switzerland.

Epidemics 2021 12 9;37:100480. Epub 2021 Aug 9.

Functional Genomics Center Zurich, ETH Zürich and University of Zurich, Zurich, Switzerland.

Background: In December 2020, the United Kingdom (UK) reported a SARS-CoV-2 Variant of Concern (VoC) which is now named B.1.1.7. Based on initial data from the UK and later data from other countries, this variant was estimated to have a transmission fitness advantage of around 40-80 % (Volz et al., 2021; Leung et al., 2021; Davies et al., 2021).

Aim: This study aims to estimate the transmission fitness advantage and the effective reproductive number of B.1.1.7 through time based on data from Switzerland.

Methods: We generated whole genome sequences from 11.8 % of all confirmed SARS-CoV-2 cases in Switzerland between 14 December 2020 and 11 March 2021. Based on these data, we determine the daily frequency of the B.1.1.7 variant and quantify the variant's transmission fitness advantage on a national and a regional scale.

Results: We estimate B.1.1.7 had a transmission fitness advantage of 43-52 % compared to the other variants circulating in Switzerland during the study period. Further, we estimate B.1.1.7 had a reproductive number above 1 from 01 January 2021 until the end of the study period, compared to below 1 for the other variants. Specifically, we estimate the reproductive number for B.1.1.7 was 1.24 [1.07-1.41] from 01 January until 17 January 2021 and 1.18 [1.06-1.30] from 18 January until 01 March 2021 based on the whole genome sequencing data. From 10 March to 16 March 2021, once B.1.1.7 was dominant, we estimate the reproductive number was 1.14 [1.00-1.26] based on all confirmed cases. For reference, Switzerland applied more non-pharmaceutical interventions to combat SARS-CoV-2 on 18 January 2021 and lifted some measures again on 01 March 2021.

Conclusion: The observed increase in B.1.1.7 frequency in Switzerland during the study period is as expected based on observations in the UK. In absolute numbers, B.1.1.7 increased exponentially with an estimated doubling time of around 2-3.5 weeks. To monitor the ongoing spread of B.1.1.7, our plots are available online.
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http://dx.doi.org/10.1016/j.epidem.2021.100480DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8452947PMC
December 2021

Microbiota-derived metabolites inhibit virulent subpopulation development by acting on single-cell behaviors.

Proc Natl Acad Sci U S A 2021 08;118(31)

Department of Environmental Systems Science, ETH Zürich, Zürich 8092, Switzerland.

spp. express pathogenicity island 1 Type III Secretion System 1 (T3SS-1) genes to mediate the initial phase of interaction with their host. Prior studies indicate short-chain fatty acids, microbial metabolites at high concentrations in the gastrointestinal tract, limit population-level T3SS-1 gene expression. However, only a subset of cells in a population express these genes, suggesting short-chain fatty acids could decrease T3SS-1 population-level expression by acting on per-cell expression or the proportion of expressing cells. Here, we combine single-cell, theoretical, and molecular approaches to address the effect of short-chain fatty acids on T3SS-1 expression. Our in vitro results show short-chain fatty acids do not repress T3SS-1 expression by individual cells. Rather, these compounds act to selectively slow the growth of T3SS-1-expressing cells, ultimately decreasing their frequency in the population. Further experiments indicate slowed growth arises from short-chain fatty acid-mediated depletion of the proton motive force. By influencing the T3SS-1 cell-type proportions, our findings imply gut microbial metabolites act on cooperation between the two cell types and ultimately influence 's capacity to establish within a host.
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http://dx.doi.org/10.1073/pnas.2103027118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346864PMC
August 2021

A distinct growth physiology enhances bacterial growth under rapid nutrient fluctuations.

Nat Commun 2021 06 16;12(1):3662. Epub 2021 Jun 16.

Institute of Environmental Engineering, ETH Zürich, Zürich, Switzerland.

It has long been known that bacteria coordinate their physiology with their nutrient environment, yet our current understanding offers little intuition for how bacteria respond to the second-to-minute scale fluctuations in nutrient concentration characteristic of many microbial habitats. To investigate the effects of rapid nutrient fluctuations on bacterial growth, we couple custom microfluidics with single-cell microscopy to quantify the growth rate of E. coli experiencing 30 s to 60 min nutrient fluctuations. Compared to steady environments of equal average concentration, fluctuating environments reduce growth rate by up to 50%. However, measured reductions in growth rate are only 38% of the growth loss predicted from single nutrient shifts. This enhancement derives from the distinct growth response of cells grown in environments that fluctuate rather than shift once. We report an unexpected physiology adapted for growth in nutrient fluctuations and implicate nutrient timescale as a critical environmental parameter beyond nutrient identity and concentration.
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http://dx.doi.org/10.1038/s41467-021-23439-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209047PMC
June 2021

Short-range quorum sensing controls horizontal gene transfer at micron scale in bacterial communities.

Nat Commun 2021 04 19;12(1):2324. Epub 2021 Apr 19.

The Shmunis School of Biomedicine and Cancer Research, Tel-Aviv University, Tel-Aviv, Israel.

In bacterial communities, cells often communicate by the release and detection of small diffusible molecules, a process termed quorum-sensing. Signal molecules are thought to broadly diffuse in space; however, they often regulate traits such as conjugative transfer that strictly depend on the local community composition. This raises the question how nearby cells within the community can be detected. Here, we compare the range of communication of different quorum-sensing systems. While some systems support long-range communication, we show that others support a form of highly localized communication. In these systems, signal molecules propagate no more than a few microns away from signaling cells, due to the irreversible uptake of the signal molecules from the environment. This enables cells to accurately detect micron scale changes in the community composition. Several mobile genetic elements, including conjugative elements and phages, employ short-range communication to assess the fraction of susceptible host cells in their vicinity and adaptively trigger horizontal gene transfer in response. Our results underscore the complex spatial biology of bacteria, which can communicate and interact at widely different spatial scales.
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http://dx.doi.org/10.1038/s41467-021-22649-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055654PMC
April 2021

Author Correction: Short-range interactions govern the dynamics and functions of microbial communities.

Nat Ecol Evol 2021 May;5(5):701

Department of Environmental Systems Science, ETH Zurich, Zurich, Switzerland.

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http://dx.doi.org/10.1038/s41559-021-01430-2DOI Listing
May 2021

Nutrient complexity triggers transitions between solitary and colonial growth in bacterial populations.

ISME J 2021 09 17;15(9):2614-2626. Epub 2021 Mar 17.

Department of Environmental Systems Sciences, Microbial Systems Ecology Group, Institute of Biogeochemistry and Pollutant Dynamics, ETH-Zurich, Zurich, Switzerland.

Microbial populations often experience fluctuations in nutrient complexity in their natural environment such as between high molecular weight polysaccharides and simple monosaccharides. However, it is unclear if cells can adopt growth behaviors that allow individuals to optimally respond to differences in nutrient complexity. Here, we directly control nutrient complexity and use quantitative single-cell analysis to study the growth dynamics of individuals within populations of the aquatic bacterium Caulobacter crescentus. We show that cells form clonal microcolonies when growing on the polysaccharide xylan, which is abundant in nature and degraded using extracellular cell-linked enzymes; and disperse to solitary growth modes when the corresponding monosaccharide xylose becomes available or nutrients are exhausted. We find that the cellular density required to achieve maximal growth rates is four-fold higher on xylan than on xylose, indicating that aggregating is advantageous on polysaccharides. When collectives on xylan are transitioned to xylose, cells start dispersing, indicating that colony formation is no longer beneficial and solitary behaviors might serve to reduce intercellular competition. Our study demonstrates that cells can dynamically tune their behaviors when nutrient complexity fluctuates, elucidates the quantitative advantages of distinct growth behaviors for individual cells and indicates why collective growth modes are prevalent in microbial populations.
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http://dx.doi.org/10.1038/s41396-021-00953-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397785PMC
September 2021

Plasmid- and strain-specific factors drive variation in ESBL-plasmid spread in vitro and in vivo.

ISME J 2021 03 4;15(3):862-878. Epub 2020 Nov 4.

Institute of Integrative Biology, Department of Environmental Systems Science, ETH Zurich, Zurich, Switzerland.

Horizontal gene transfer, mediated by conjugative plasmids, is a major driver of the global rise of antibiotic resistance. However, the relative contributions of factors that underlie the spread of plasmids and their roles in conjugation in vivo are unclear. To address this, we investigated the spread of clinical Extended Spectrum Beta-Lactamase (ESBL)-producing plasmids in the absence of antibiotics in vitro and in the mouse intestine. We hypothesised that plasmid properties would be the primary determinants of plasmid spread and that bacterial strain identity would also contribute. We found clinical Escherichia coli strains natively associated with ESBL-plasmids conjugated to three distinct E. coli strains and one Salmonella enterica serovar Typhimurium strain. Final transconjugant frequencies varied across plasmid, donor, and recipient combinations, with qualitative consistency when comparing transfer in vitro and in vivo in mice. In both environments, transconjugant frequencies for these natural strains and plasmids covaried with the presence/absence of transfer genes on ESBL-plasmids and were affected by plasmid incompatibility. By moving ESBL-plasmids out of their native hosts, we showed that donor and recipient strains also modulated transconjugant frequencies. This suggests that plasmid spread in the complex gut environment of animals and humans can be predicted based on in vitro testing and genetic data.
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http://dx.doi.org/10.1038/s41396-020-00819-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8026971PMC
March 2021

Rapid evolution destabilizes species interactions in a fluctuating environment.

ISME J 2021 02 6;15(2):450-460. Epub 2020 Oct 6.

Department of Environmental Systems Sciences, ETH Zürich, 8092, Zürich, Switzerland.

Positive species interactions underlie the functioning of ecosystems. Given their importance, it is crucial to understand the stability of positive interactions over evolutionary timescales, in both constant and fluctuating environments; e.g., environments interrupted with periods of competition. We addressed this question using a two-species microbial system in which we modulated interactions according to the nutrient provided. We evolved in parallel four experimental replicates of species growing in isolation or together in consortia for 200 generations in both a constant and fluctuating environment with daily changes between commensalism and competition. We sequenced full genomes of single clones isolated at different time points during the experiment. We found that the two species coexisted over 200 generations in the constant commensal environment. In contrast, in the fluctuating environment, coexistence broke down when one of the species went extinct in two out of four cases. We showed that extinction was highly deterministic: when we replayed the evolution experiment from an intermediate time point we repeatably reproduced species extinction. We further show that these dynamics were driven by adaptive mutations in a small set of genes. In conclusion, in a fluctuating environment, rapid evolution destabilizes the long-term stability of positive pairwise interactions.
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http://dx.doi.org/10.1038/s41396-020-00787-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8027891PMC
February 2021

Wide lag time distributions break a trade-off between reproduction and survival in bacteria.

Proc Natl Acad Sci U S A 2020 08 15;117(31):18729-18736. Epub 2020 Jul 15.

Institute of Biogeochemistry and Pollutant Dynamics, Department of Environmental Systems Science, ETH Zurich, 8092 Zurich, Switzerland.

Many microorganisms face a fundamental trade-off between reproduction and survival: Rapid growth boosts population size but makes microorganisms sensitive to external stressors. Here, we show that starved bacteria encountering new resources can break this trade-off by evolving phenotypic heterogeneity in lag time. We quantify the distribution of single-cell lag times of populations of starved and show that population growth after starvation is primarily determined by the cells with shortest lag due to the exponential nature of bacterial population dynamics. As a consequence, cells with long lag times have no substantial effect on population growth resumption. However, we observe that these cells provide tolerance to stressors such as antibiotics. This allows an isogenic population to break the trade-off between reproduction and survival. We support this argument with an evolutionary model which shows that bacteria evolve wide lag time distributions when both rapid growth resumption and survival under stressful conditions are under selection. Our results can explain the prevalence of antibiotic tolerance by lag and demonstrate that the benefits of phenotypic heterogeneity in fluctuating environments are particularly high when minorities with extreme phenotypes dominate population dynamics.
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http://dx.doi.org/10.1073/pnas.2003331117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7414188PMC
August 2020

Dissection of the mutation accumulation process during bacterial range expansions.

BMC Genomics 2020 Mar 23;21(1):253. Epub 2020 Mar 23.

CMPG, Institute of Ecology an Evolution, University of Berne, Baltzerstrasse 6, 3012, Berne, Switzerland.

Background: Recent experimental work has shown that the evolutionary dynamics of bacteria expanding across space can differ dramatically from what we expect under well-mixed conditions. During spatial expansion, deleterious mutations can accumulate due to inefficient selection on the expansion front, potentially interfering with and modifying adaptive evolutionary processes.

Results: We used whole genome sequencing to follow the genomic evolution of 10 mutator Escherichia coli lines during 39 days ( ~ 1650 generations) of a spatial expansion, which allowed us to gain a temporal perspective on the interaction of adaptive and non-adaptive evolutionary processes during range expansions. We used elastic net regression to infer the positive or negative effects of mutations on colony growth. The colony size, measured after three day of growth, decreased at the end of the experiment in all 10 lines, and mutations accumulated at a nearly constant rate over the whole experiment. We find evidence that beneficial mutations accumulate primarily at an early stage of the experiment, leading to a non-linear change of colony size over time. Indeed, the rate of colony size expansion remains almost constant at the beginning of the experiment and then decreases after ~ 12 days of evolution. We also find that beneficial mutations are enriched in genes encoding transport proteins, and genes coding for the membrane structure, whereas deleterious mutations show no enrichment for any biological process.

Conclusions: Our experiment shows that beneficial mutations target specific biological functions mostly involved in inter or extra membrane processes, whereas deleterious mutations are randomly distributed over the whole genome. It thus appears that the interaction between genetic drift and the availability or depletion of beneficial mutations determines the change in fitness of bacterial populations during range expansion.
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http://dx.doi.org/10.1186/s12864-020-6676-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7092555PMC
March 2020

Publisher Correction: Short-range interactions govern the dynamics and functions of microbial communities.

Nat Ecol Evol 2020 Apr;4(4):663

Department of Environmental Systems Science, ETH Zurich, Zurich, Switzerland.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.
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http://dx.doi.org/10.1038/s41559-020-1175-9DOI Listing
April 2020

Understanding the evolution of interspecies interactions in microbial communities.

Philos Trans R Soc Lond B Biol Sci 2020 05 23;375(1798):20190256. Epub 2020 Mar 23.

Institute of Biogeochemistry and Pollutant Dynamics, Department of Environmental Systems Science, ETH Zürich, Zürich, Switzerland.

Microbial communities are complex multi-species assemblages that are characterized by a multitude of interspecies interactions, which can range from mutualism to competition. The overall sign and strength of interspecies interactions have important consequences for emergent community-level properties such as productivity and stability. It is not well understood how interspecies interactions change over evolutionary timescales. Here, we review the empirical evidence that evolution is an important driver of microbial community properties and dynamics on timescales that have traditionally been regarded as purely ecological. Next, we briefly discuss different modelling approaches to study evolution of communities, emphasizing the similarities and differences between evolutionary and ecological perspectives. We then propose a simple conceptual model for the evolution of interspecies interactions in communities. Specifically, we propose that to understand the evolution of interspecies interactions, it is important to distinguish between direct and indirect fitness effects of a mutation. We predict that in well-mixed environments, traits will be selected exclusively for their direct fitness effects, while in spatially structured environments, traits may also be selected for their indirect fitness effects. Selection of indirectly beneficial traits should result in an increase in interaction strength over time, while selection of directly beneficial traits should not have such a systematic effect. We tested our intuitions using a simple quantitative model and found support for our hypotheses. The next step will be to test these hypotheses experimentally and provide input for a more refined version of the model in turn, thus closing the scientific cycle of models and experiments. This article is part of the theme issue 'Conceptual challenges in microbial community ecology'.
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http://dx.doi.org/10.1098/rstb.2019.0256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7133538PMC
May 2020

Short-range interactions govern the dynamics and functions of microbial communities.

Nat Ecol Evol 2020 03 10;4(3):366-375. Epub 2020 Feb 10.

Department of Environmental Systems Science, ETH Zurich, Zurich, Switzerland.

Communities of interacting microorganisms play important roles across all habitats on Earth. These communities typically consist of a large number of species that perform different metabolic processes. The functions of microbial communities ultimately emerge from interactions between these different microorganisms. To understand the dynamics and functions of microbial communities, we thus need to know the nature and strength of these interactions. Here, we quantified the interaction strength between individual cells in microbial communities. We worked with synthetic communities of Escherichia coli bacteria that exchange metabolites to grow. We combined single-cell growth rate measurements with mathematical modelling to quantify metabolic interactions between individual cells and to map the spatial interaction network in these communities. We found that cells only interact with other cells in their immediate neighbourhood. This short interaction range limits the coupling between different species and reduces their ability to perform metabolic processes collectively. Our experiments and models demonstrate that the spatial scale of biotic interaction plays a fundamental role in shaping the ecological dynamics of communities and the functioning of ecosystems.
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http://dx.doi.org/10.1038/s41559-019-1080-2DOI Listing
March 2020

Environmental drivers of metabolic heterogeneity in clonal microbial populations.

Curr Opin Biotechnol 2020 04 23;62:202-211. Epub 2019 Dec 23.

ETH Zurich, Institute of Biogeochemistry and Pollutant Dynamics, Zurich, Switzerland; Eawag, Department of Environmental Microbiology, Dubendorf, Switzerland.

Microorganisms perform multiple metabolic functions that shape the global cycling of elements, health and disease of their host organisms, and biotechnological processes. The rates, at which different metabolic activities are performed by individual cells, can vary between genetically identical cells within clonal populations. While the molecular mechanisms that result in such metabolic heterogeneity have attracted considerable interest, the environmental conditions that shape heterogeneity and its consequences have received attention only in recent years. Here, we review the environmental drivers that lead to metabolic heterogeneity with a focus on nutrient limitation, temporal fluctuations and spatial structure, and the functional consequences of such heterogeneity. We highlight studies using single-cell methods that allow direct investigation of metabolic heterogeneity and discuss the relevance of metabolic heterogeneity in complex microbial communities.
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http://dx.doi.org/10.1016/j.copbio.2019.11.018DOI Listing
April 2020

Emergent microscale gradients give rise to metabolic cross-feeding and antibiotic tolerance in clonal bacterial populations.

Philos Trans R Soc Lond B Biol Sci 2019 11 7;374(1786):20190080. Epub 2019 Oct 7.

Institute of Biogeochemistry and Pollutant Dynamics, Department of Environmental Systems Science, ETH Zurich, Universitätstrasse 16, 8092 Zürich, Switzerland.

Bacteria often live in spatially structured groups such as biofilms. In these groups, cells can collectively generate gradients through the uptake and release of compounds. In turn, individual cells adapt their activities to the environment shaped by the whole group. Here, we studied how these processes can generate phenotypic variation in clonal populations and how this variation contributes to the resilience of the population to antibiotics. We grew two-dimensional populations of in microfluidic chambers where limiting amounts of glucose were supplied from one side. We found that the collective metabolic activity of cells created microscale gradients where nutrient concentration varied over a few cell lengths. As a result, growth rates and gene expression levels varied strongly between neighbouring cells. Furthermore, we found evidence for a metabolic cross-feeding interaction between glucose-fermenting and acetate-respiring subpopulations. Finally, we found that subpopulations of cells were able to survive an antibiotic pulse that was lethal in well-mixed conditions, likely due to the presence of a slow-growing subpopulation. Our work shows that emergent metabolic gradients can have important consequences for the functionality of bacterial populations as they create opportunities for metabolic interactions and increase the populations' tolerance to environmental stressors. This article is part of a discussion meeting issue 'Single cell ecology'.
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http://dx.doi.org/10.1098/rstb.2019.0080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6792440PMC
November 2019

Light-Induced Mechanistic Divergence in Gold(I) Catalysis: Revisiting the Reactivity of Diazonium Salts.

Angew Chem Int Ed Engl 2019 Nov 11;58(47):16988-16993. Epub 2019 Oct 11.

Molecular Inorganic Chemistry, Stratingh Institute for Chemistry, Faculty of Science and Engineering, University of Groningen, Nijenborgh 4, 9747, AG, Groningen, The Netherlands.

In a systematic study of the Au-catalyzed reaction of o-alkynylphenols with aryldiazonium salts, we find that essentially the same reaction conditions lead to a change in mechanism when a light source is applied. If the reaction is carried out at room temperature using a Au catalyst, the diazonium salt undergoes electrophilic deauration of a vinyl Au intermediate and provides access to substituted azobenzofurans. If the reaction mixture is irradiated with blue LED light, C-C bond formation due to N -extrusion from the diazonium salt is realized selectively, using the same starting materials without the need for an additional photo(redox) catalyst under aerobic conditions. We report a series of experiments demonstrating that the same vinyl Au intermediate is capable of producing the observed products under photolytic and thermal conditions. The finding that a vinyl Au complex can directly, without the need for an additional photo(redox) catalyst, result in C-C bond formation under photolytic conditions is contrary to the proposed mechanistic pathways suggested in the literature till date and highlights that the role of oxidation state changes in photoredox catalysis involving Au is thus far only poorly understood and may hold surprises for the future. Computational results indicate that photochemical activation can occur directly from a donor-acceptor complex formed between the vinyl Au intermediate and the diazonium salt.
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http://dx.doi.org/10.1002/anie.201908268DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6899485PMC
November 2019

Stochastic Gene Expression Influences the Selection of Antibiotic Resistance Mutations.

Mol Biol Evol 2020 Jan;37(1):58-70

Institute of Integrative Biology, ETH Zürich, Zürich, Switzerland.

Bacteria can resist antibiotics by expressing enzymes that remove or deactivate drug molecules. Here, we study the effects of gene expression stochasticity on efflux and enzymatic resistance. We construct an agent-based model that stochastically simulates multiple biochemical processes in the cell and we observe the growth and survival dynamics of the cell population. Resistance-enhancing mutations are introduced by varying parameters that control the enzyme expression or efficacy. We find that stochastic gene expression can cause complex dynamics in terms of survival and extinction for these mutants. Regulatory mutations, which augment the frequency and duration of resistance gene transcription, can provide limited resistance by increasing mean expression. Structural mutations, which modify the enzyme or efflux efficacy, provide most resistance by improving the binding affinity of the resistance protein to the antibiotic; increasing the enzyme's catalytic rate alone may contribute to resistance if drug binding is not rate limiting. Overall, we identify conditions where regulatory mutations are selected over structural mutations, and vice versa. Our findings show that stochastic gene expression is a key factor underlying efflux and enzymatic resistances and should be taken into consideration in future antibiotic research.
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http://dx.doi.org/10.1093/molbev/msz199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6984361PMC
January 2020

Microbial life cycles link global modularity in regulation to mosaic evolution.

Nat Ecol Evol 2019 08 22;3(8):1184-1196. Epub 2019 Jul 22.

Department of Evolutionary Biology and Environmental Studies, University of Zürich, Zürich, Switzerland.

Microbes are exposed to changing environments, to which they can respond by adopting various lifestyles such as swimming, colony formation or dormancy. These lifestyles are often studied in isolation, thereby giving a fragmented view of the life cycle as a whole. Here, we study lifestyles in the context of this whole. We first use machine learning to reconstruct the expression changes underlying life cycle progression in the bacterium Bacillus subtilis, based on hundreds of previously acquired expression profiles. This yields a timeline that reveals the modular organization of the life cycle. By analysing over 380 Bacillales genomes, we then show that life cycle modularity gives rise to mosaic evolution in which life stages such as motility and sporulation are conserved and lost as discrete units. We postulate that this mosaic conservation pattern results from habitat changes that make these life stages obsolete or detrimental. Indeed, when evolving eight distinct Bacillales strains and species under laboratory conditions that favour colony growth, we observe rapid and parallel losses of the sporulation life stage across species, induced by mutations that affect the same global regulator. We conclude that a life cycle perspective is pivotal to understanding the causes and consequences of modularity in both regulation and evolution.
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http://dx.doi.org/10.1038/s41559-019-0939-6DOI Listing
August 2019

Metabolic activity affects the response of single cells to a nutrient switch in structured populations.

J R Soc Interface 2019 07 10;16(156):20190182. Epub 2019 Jul 10.

1 Department of Environmental Systems Science, Institute of Biogeochemistry and Pollutant Dynamics, ETH Zurich , Universitätstrasse 16, 8092 Zürich , Switzerland.

Microbes live in ever-changing environments where they need to adapt their metabolism to different nutrient conditions. Many studies have characterized the response of genetically identical cells to nutrient switches in homogeneous cultures; however, in nature, microbes often live in spatially structured groups such as biofilms where cells can create metabolic gradients by consuming and releasing nutrients. Consequently, cells experience different local microenvironments and vary in their phenotype. How does this phenotypic variation affect the ability of cells to cope with nutrient switches? Here, we address this question by growing dense populations of Escherichia coli in microfluidic chambers and studying a switch from glucose to acetate at the single-cell level. Before the switch, cells vary in their metabolic activity: some grow on glucose, while others cross-feed on acetate. After the switch, only few cells can resume growth after a period of lag. The probability to resume growth depends on a cells' phenotype prior to the switch: it is highest for cells cross-feeding on acetate, while it depends in a non-monotonic way on the growth rate for cells growing on glucose. Our results suggest that the strong phenotypic variation in spatially structured populations might enhance their ability to cope with fluctuating environments.
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http://dx.doi.org/10.1098/rsif.2019.0182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6685030PMC
July 2019

Mutational and Selective Processes Involved in Evolution during Bacterial Range Expansions.

Mol Biol Evol 2019 10;36(10):2313-2327

CMPG, Institute of Ecology an Evolution, University of Berne, Berne, Switzerland.

Bacterial populations have been shown to accumulate deleterious mutations during spatial expansions that overall decrease their fitness and ability to grow. However, it is unclear if and how they can respond to selection in face of this mutation load. We examine here if artificial selection can counteract the negative effects of range expansions. We examined the molecular evolution of 20 mutator lines selected for fast expansions (SEL) and compared them to 20 other mutator lines freely expanding without artificial selection (CONTROL). We find that the colony size of all 20 SEL lines have increased relative to the ancestral lines, unlike CONTROL lines, showing that enough beneficial mutations are produced during spatial expansions to counteract the negative effect of expansion load. Importantly, SEL and CONTROL lines have similar numbers of mutations indicating that they evolved for the same number of generations and that increased fitness is not due to a purging of deleterious mutations. We find that loss of function mutations better explain the increased colony size of SEL lines than nonsynonymous mutations or a combination of the two. Interestingly, most loss of function mutations are found in simple sequence repeats (SSRs) located in genes involved in gene regulation and gene expression. We postulate that such potentially reversible mutations could play a major role in the rapid adaptation of bacteria to changing environmental conditions by shutting down expensive genes and adjusting gene expression.
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http://dx.doi.org/10.1093/molbev/msz148DOI Listing
October 2019

Disseminating antibiotic resistance during treatment.

Science 2019 05;364(6442):737-738

Department of Environmental Systems Science, ETH Zurich, 8092 Zurich, Switzerland.

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http://dx.doi.org/10.1126/science.aax6620DOI Listing
May 2019

Publisher Correction: Definitions and guidelines for research on antibiotic persistence.

Nat Rev Microbiol 2019 Jul;17(7):460

Division of Infectious Diseases, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

In Figure 2b, the minimal duration for killing (MDK) 99% of tolerant cells was erroneously labelled as MDK99.99 instead of MDK99. This has now been corrected in all versions of the Review. The publisher apologizes to the authors and to readers for this error.
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http://dx.doi.org/10.1038/s41579-019-0207-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609342PMC
July 2019

Definitions and guidelines for research on antibiotic persistence.

Nat Rev Microbiol 2019 07;17(7):441-448

Division of Infectious Diseases, University Hospital Zurich, University of Zurich, Zurich, Switzerland.

Increasing concerns about the rising rates of antibiotic therapy failure and advances in single-cell analyses have inspired a surge of research into antibiotic persistence. Bacterial persister cells represent a subpopulation of cells that can survive intensive antibiotic treatment without being resistant. Several approaches have emerged to define and measure persistence, and it is now time to agree on the basic definition of persistence and its relation to the other mechanisms by which bacteria survive exposure to bactericidal antibiotic treatments, such as antibiotic resistance, heteroresistance or tolerance. In this Consensus Statement, we provide definitions of persistence phenomena, distinguish between triggered and spontaneous persistence and provide a guide to measuring persistence. Antibiotic persistence is not only an interesting example of non-genetic single-cell heterogeneity, it may also have a role in the failure of antibiotic treatments. Therefore, it is our hope that the guidelines outlined in this article will pave the way for better characterization of antibiotic persistence and for understanding its relevance to clinical outcomes.
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http://dx.doi.org/10.1038/s41579-019-0196-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7136161PMC
July 2019

Why microbes secrete molecules to modify their environment: the case of iron-chelating siderophores.

J R Soc Interface 2019 01;16(150):20180674

3 Institute of Biogeochemistry and Pollutant Dynamics, Swiss Federal Institute of Technology Zurich (ETH Zurich) , Zurich , Switzerland.

Many microorganisms secrete molecules that interact with resources outside of the cell. This includes, for example, enzymes that degrade polymers like chitin, and chelators that bind trace metals like iron. In contrast to direct uptake via the cell surface, such release strategies entail the risk of losing the secreted molecules to environmental sinks, including 'cheating' genotypes. Nevertheless, such secretion strategies are widespread, even in the well-mixed marine environment. Here, we investigate the benefits of a release strategy whose efficiency has frequently been questioned: iron uptake in the ocean by secretion of iron chelators called siderophores. We asked the question whether the release itself is essential for the function of siderophores, which could explain why this risky release strategy is widespread. We developed a reaction-diffusion model to determine the impact of siderophore release on iron uptake from the predominant iron sources in marine environments, colloidal or particulate iron, formed due to poor iron solubility. We found that release of siderophores is essential to accelerate iron uptake, as secreted siderophores transform slowly diffusing large iron particles to small, quickly diffusing iron-siderophore complexes. In addition, we found that cells can synergistically share their siderophores, depending on their distance and the size of the iron sources. Our study helps understand why release of siderophores is so widespread: even though a large fraction of siderophores is lost, the solubilization of iron through secreted siderophores can efficiently increase iron uptake, especially if siderophores are produced cooperatively by several cells. Overall, resource uptake mediated via release of molecules transforming their substrate could be essential to overcome diffusion limitation specifically in the cases of large, aggregated resources. In addition, we find that including the reaction of the released molecule with the substrate can impact the result of cooperative and competitive interactions, making our model also relevant for release-based uptake of other substrates.
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http://dx.doi.org/10.1098/rsif.2018.0674DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6364635PMC
January 2019

Individual- versus group-optimality in the production of secreted bacterial compounds.

Evolution 2019 04 28;73(4):675-688. Epub 2019 Feb 28.

Department of Plant and Microbial Biology, University of Zürich, Zürich, 8057, Switzerland.

How unicellular organisms optimize the production of compounds is a fundamental biological question. While it is typically thought that production is optimized at the individual-cell level, secreted compounds could also allow for optimization at the group level, leading to a division of labor where a subset of cells produces and shares the compound with everyone. Using mathematical modeling, we show that the evolution of such division of labor depends on the cost function of compound production. Specifically, for any trait with saturating benefits, linear costs promote the evolution of uniform production levels across cells. Conversely, production costs that diminish with higher output levels favor the evolution of specialization-especially when compound shareability is high. When experimentally testing these predictions with pyoverdine, a secreted iron-scavenging compound produced by Pseudomonas aeruginosa, we found linear costs and, consistent with our model, detected uniform pyoverdine production levels across cells. We conclude that for shared compounds with saturating benefits, the evolution of division of labor is facilitated by a diminishing cost function. More generally, we note that shifts in the level of selection from individuals to groups do not solely require cooperation, but critically depend on mechanistic factors, including the distribution of compound synthesis costs.
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http://dx.doi.org/10.1111/evo.13701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6467250PMC
April 2019

The rate of environmental fluctuations shapes ecological dynamics in a two-species microbial system.

Ecol Lett 2019 May 21;22(5):838-846. Epub 2019 Feb 21.

Department of Environmental Systems Sciences, ETH Zürich, Zürich, Switzerland.

Species interactions change when the external conditions change. How these changes affect microbial community properties is an open question. We address this question using a two-species consortium in which species interactions change from exploitation to competition depending on the carbon source provided. We built a mathematical model and calibrated it using single-species growth measurements. This model predicted that low frequencies of change between carbon sources lead to species loss, while intermediate and high frequencies of change maintained both species. We experimentally confirmed these predictions by growing co-cultures in fluctuating environments. These findings complement more established concepts of a diversity peak at intermediate disturbance frequencies. They also provide a mechanistic understanding for how the dynamics at the community level emerges from single-species behaviours and interspecific interactions. Our findings suggest that changes in species interactions can profoundly impact the ecological dynamics and properties of microbial systems.
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http://dx.doi.org/10.1111/ele.13241DOI Listing
May 2019

Prolonged bacterial lag time results in small colony variants that represent a sub-population of persisters.

Nat Commun 2018 10 4;9(1):4074. Epub 2018 Oct 4.

Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, 8091, Switzerland.

Persisters are a subpopulation of bacteria that are not killed by antibiotics even though they lack genetic resistance. Here we provide evidence that persisters can manifest as small colony variants (SCVs) in clinical infections. We analyze growth kinetics of Staphylococcus aureus sampled from in vivo conditions and in vitro stress conditions that mimic growth in host compartments. We report that SCVs arise as a result of a long lag time, and that this phenotype emerges de novo during the growth phase in various stress conditions including abscesses and acidic media. We further observe that long lag time correlates with antibiotic usage. These observations suggest that treatment strategies should be carefully tailored to address bacterial persisters in clinics.
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http://dx.doi.org/10.1038/s41467-018-06527-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6172231PMC
October 2018

Division of labor in bacteria.

Elife 2018 06 29;7. Epub 2018 Jun 29.

Department of Environmental Systems Sciences, ETH Zurich, Zurich, Switzerland.

The emergence of subpopulations that perform distinct metabolic roles has been observed in populations of genetically identical bacteria.
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http://dx.doi.org/10.7554/eLife.38578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6025956PMC
June 2018

Function and functional redundancy in microbial systems.

Nat Ecol Evol 2018 06 16;2(6):936-943. Epub 2018 Apr 16.

Biodiversity Research Centre, University of British Columbia, Vancouver, British Columbia, Canada.

Microbial communities often exhibit incredible taxonomic diversity, raising questions regarding the mechanisms enabling species coexistence and the role of this diversity in community functioning. On the one hand, many coexisting but taxonomically distinct microorganisms can encode the same energy-yielding metabolic functions, and this functional redundancy contrasts with the expectation that species should occupy distinct metabolic niches. On the other hand, the identity of taxa encoding each function can vary substantially across space or time with little effect on the function, and this taxonomic variability is frequently thought to result from ecological drift between equivalent organisms. Here, we synthesize the powerful paradigm emerging from these two patterns, connecting the roles of function, functional redundancy and taxonomy in microbial systems. We conclude that both patterns are unlikely to be the result of ecological drift, but are inevitable emergent properties of open microbial systems resulting mainly from biotic interactions and environmental and spatial processes.
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http://dx.doi.org/10.1038/s41559-018-0519-1DOI Listing
June 2018
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