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.