Understanding the conditions that promote the maintenance of cooperation is a classic problem in evolutionary biology. The essence of this dilemma is captured by the 'tragedy of the commons': how can a group of individuals that exploit resources in a cooperative manner resist invasion by 'cheaters' who selfishly use common resources to maximize their individual reproduction at the expense of the group? Here, we investigate this conflict through experimental competitions between isogenic cheater and cooperator strains of yeast with alternative pathways of glucose metabolism, and by using mathematical models of microbial biochemistry. We show that both coexistence and competitive exclusion are possible outcomes of this conflict, depending on the spatial and temporal structure of the environment. Both of these outcomes are driven by trade-offs between the rate and efficiency of conversion of resources into offspring that are mediated by metabolic intermediates.
It is commonly assumed that the world would be best off if everyone co-operates. Experimental and mathematical analysis of “co-operation” in yeast show why this isn't always the case.
How is diversity maintained? While environmental heterogeneity is considered important 1 , diversity in seemingly homogeneous environments is nonetheless observed 2 . This, it is assumed, must either be owing to weak selection, mutational input or a fitness advantage to genotypes when rare 1 .Here we demonstrate the possibility of a new general mechanism of stable diversity maintenance, one that stems from metabolic and physiological trade--offs 3 . The model requires that such trade--offs translate into a fitness landscape in which the most fit has unfit near--mutational neighbours, while a lower fitness peak exists that is more mutationally robust. The "survival of the fittest" applies at low mutation rates, giving way to "survival of the flattest 4,5,6 " at high mutation rates. However, as a consequence of quasispecies--level negative frequency--dependent selection and differences in mutational robustness we observe a transition zone in which both fittest and flattest co--exist. While diversity maintenance is possible for simple organisms in simple environments, the more trade--offs the wider the maintenance zone. The principle may be applied to lineages within a species or species within a community, potentially explaining why competitive exclusion need not be observed in homogeneous environments. This principle predicts the enigmatic richness of metabolic strategies in clonal bacteria 7 and questions the safety of lethal mutagenesis 8,9 as an antimicrobial treatment.
We need to find ways of enhancing the potency of existing antibiotics, and, with this in mind, we begin with an unusual question: how low can antibiotic dosages be and yet bacterial clearance still be observed? Seeking to optimise the simultaneous use of two antibiotics, we use the minimal dose at which clearance is observed in an in vitro experimental model of antibiotic treatment as a criterion to distinguish the best and worst treatments of a bacterium, Escherichia coli. Our aim is to compare a combination treatment consisting of two synergistic antibiotics to so-called sequential treatments in which the choice of antibiotic to administer can change with each round of treatment. Using mathematical predictions validated by the E. coli treatment model, we show that clearance of the bacterium can be achieved using sequential treatments at antibiotic dosages so low that the equivalent two-drug combination treatments are ineffective. Seeking to treat the bacterium in testing circumstances, we purposefully study an E. coli strain that has a multidrug pump encoded in its chromosome that effluxes both antibiotics. Genomic amplifications that increase the number of pumps expressed per cell can cause the failure of high-dose combination treatments, yet, as we show, sequentially treated populations can still collapse. However, dual resistance due to the pump means that the antibiotics must be carefully deployed and not all sublethal sequential treatments succeed. A screen of 136 96-h-long sequential treatments determined five of these that could clear the bacterium at sublethal dosages in all replicate populations, even though none had done so by 24 h. These successes can be attributed to a collateral sensitivity whereby cross-resistance due to the duplicated pump proves insufficient to stop a reduction in E. coli growth rate following drug exchanges, a reduction that proves large enough for appropriately chosen drug switches to clear the bacterium.
Understanding how populations and communities respond to competition is a central concern of ecology. A seminal theoretical solution first formalised by Levins (and re-derived in multiple fields) showed that, in theory, the form of a trade-off should determine the outcome of competition. While this has become a central postulate in ecology it has evaded experimental verification, not least because of substantial technical obstacles. We here solve the experimental problems by employing synthetic ecology. We engineer strains of Escherichia coli with fixed resource allocations enabling accurate measurement of trade-off shapes between bacterial survival and multiplication in multiple environments. A mathematical chemostat model predicts different, and experimentally verified, trajectories of gene frequency changes as a function of condition-specific trade-offs. The results support Levins' postulate and demonstrates that otherwise paradoxical alternative outcomes witnessed in subtly different conditions are predictable.
Although polymicrobial infections, caused by combinations of viruses, bacteria, fungi and parasites, are being recognised with increasing frequency, little is known about the occurrence of within-species diversity in bacterial infections and the molecular and evolutionary bases of this diversity. We used multiple approaches to study the genomic and phenotypic diversity among 226 Escherichia coli isolates from deep and closed visceral infections occurring in 19 patients. We observed genomic variability among isolates from the same site within 11 patients. This diversity was of two types, as patients were infected either by several distinct E. coli clones (4 patients) or by members of a single clone that exhibit micro-heterogeneity (11 patients); both types of diversity were present in 4 patients. A surprisingly wide continuum of antibiotic resistance, outer membrane permeability, growth rate, stress resistance, red dry and rough morphotype characteristics and virulence properties were present within the isolates of single clones in 8 of the 11 patients showing genomic micro-heterogeneity. Many of the observed phenotypic differences within clones affected the trade-off between self-preservation and nutritional competence (SPANC). We showed in 3 patients that this phenotypic variability was associated with distinct levels of RpoS in co-existing isolates. Genome mutational analysis and global proteomic comparisons in isolates from a patient revealed a star-like relationship of changes amongst clonally diverging isolates. A mathematical model demonstrated that multiple genotypes with distinct RpoS levels can co-exist as a result of the SPANC trade-off. In the cases involving infection by a single clone, we present several lines of evidence to suggest diversification during the infectious process rather than an infection by multiple isolates exhibiting a micro-heterogeneity. Our results suggest that bacteria are subject to trade-offs during an infectious process and that the observed diversity resembled results obtained in experimental evolution studies. Whatever the mechanisms leading to diversity, our results have strong medical implications in terms of the need for more extensive isolate testing before deciding on antibiotic therapies.
Understanding the evolution of microbial diversity is an important and current problem in evolutionary ecology. In this paper, we investigated the role of two established biochemical trade‐offs in microbial diversification using a model that connects ecological and evolutionary processes with fundamental aspects of biochemistry. The trade‐offs that we investigated are as follows:(1) a trade‐off between the rate and affinity of substrate transport; and (2) a trade‐off between the rate and yield of ATP production. Our model shows that these biochemical trade‐offs can drive evolutionary diversification under the simplest possible ecological conditions: a homogeneous environment containing a single limiting resource. We argue that the results of a number of microbial selection experiments are consistent with the predictions of our model.
Evolutionary trajectories are constrained by tradeoffs when mutations that benefit one life history trait incur fitness costs in other traits. As resistance to tetracycline antibiotics by increased efflux can be associated with a 10%, or more, increase in length of the Escherichia coli chromosome, we sought costs of resistance associated with doxycycline. However, it was difficult to identify any because E.coli's growth rate (r), carrying capacity (K) and drug efflux rate increased during evolutionary experiments where E.coli was exposed to doxycycline. Moreover, these improvements remained following drug withdrawal. We sought mechanisms for this seemingly unconstrained adaptation particularly as these traits ought to tradeoff according to rK selection theory. Using prokaryote and eukaryote microbes, including clinical pathogens, we therefore show r and K can tradeoff, but need not, because of 'rK trade-ups'. r and K only tradeoff in sufficiently carbon-rich environments where growth is inefficient.We then used E. coli ribosomal RNA (rrn) knockouts to determine specific mutations, namely changes in rrn operon copy number, than can simultaneously maximise r and K. The optimal genome has fewer operons, and therefore fewer functional ribosomes, than the ancestral strain. It is, therefore, unsurprising for r-adaptation in the presence of a ribosome-inhibiting antibiotic, doxycycline, to also increase population size. Although E. coli can evolve to grow faster and to larger population sizes in the presence of antibiotics when compared to their absence, we found two costs to this improvement: an elongated lag phase and the loss of stress protection genes. 1 IntroductionTradeoffs lie at the heart of a cross-kingdom research effort that seeks to explain how biodiversity is generated and maintained. [1][2][3][4][5] Two traits engage in an evolutionary tradeoff when beneficial mutations for one trait are deleterious for the other, and vice versa, and many theories agree 2,[6][7][8][9][10][11] that genetic polymorphisms are maintained when tradeoffs have an appropriate geometry. Less clear, however, are the physical, chemical and physiological forces that create tradeoffs in the first place 12 and tradeoffs needed for the theories to work can be difficult to isolate in practise. [13][14][15][16][17][18] It is essential for medicine that we understand tradeoffs. The term 'superbug' refers to a pathogenic microorganism that resists treatment by antibiotics with no apparent cost, or tradeoff, in terms of its pathogenicity. An evolutionary route to superbug status is thought to occur when a pathogen first adopts costly drug resistance mutations, a process that sees resistance traded against proliferation rate in antibiotic-free environments. Thereafter, other mutations compensate for those costs, yielding strains that are both drug resistant and capable of rapid proliferation. 19, 20 Tradeoffs are, however, sometimes observed in pathogens. A genomic study of a clinical pathogen using several antibiotic classes 21 showed res...
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