1,370 research outputs found

    Designing antibiotic cycling strategies by determining and understanding local adaptive landscapes

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    The evolution of antibiotic resistance among bacteria threatens our continued ability to treat infectious diseases. The need for sustainable strategies to cure bacterial infections has never been greater. So far, all attempts to restore susceptibility after resistance has arisen have been unsuccessful, including restrictions on prescribing [1] and antibiotic cycling [2,3]. Part of the problem may be that those efforts have implemented different classes of unrelated antibiotics, and relied on removal of resistance by random loss of resistance genes from bacterial populations (drift). Here, we show that alternating structurally similar antibiotics can restore susceptibility to antibiotics after resistance has evolved. We found that the resistance phenotypes conferred by variant alleles of the resistance gene encoding the TEM {\beta}-lactamase (blaTEM) varied greatly among 15 different {\beta}-lactam antibiotics. We captured those differences by characterizing complete adaptive landscapes for the resistance alleles blaTEM-50 and blaTEM-85, each of which differs from its ancestor blaTEM-1 by four mutations. We identified pathways through those landscapes where selection for increased resistance moved in a repeating cycle among a limited set of alleles as antibiotics were alternated. Our results showed that susceptibility to antibiotics can be sustainably renewed by cycling structurally similar antibiotics. We anticipate that these results may provide a conceptual framework for managing antibiotic resistance. This approach may also guide sustainable cycling of the drugs used to treat malaria and HIV

    Dynamics of clade diversification on the morphological hypercube

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    Understanding the relationship between taxonomic and morphological changes is important in identifying the reasons for accelerated morphological diversification early in the history of animal phyla. Here, a simple general model describing the joint dynamics of taxonomic diversity and morphological disparity is presented and applied to the data on the diversification of blastozoans. I show that the observed patterns of deceleration in clade diversification can be explicable in terms of the geometric structure of the morphospace and the effects of extinction and speciation on morphological disparity without invoking major declines in the size of morphological transitions or taxonomic turnover rates. The model allows testing of hypotheses about patterns of diversification and estimation of rates of morphological evolution. In the case of blastozoans, I find no evidence that major changes in evolutionary rates and mechanisms are responsible for the deceleration of morphological diversification seen during the period of this clade's expansion. At the same time, there is evidence for a moderate decline in overall rates of morphological diversification concordant with a major change (from positive to negative values) in the clade's growth rate.Comment: 8 pages, Latex, 2 postscript figures, submitted to Proc.R.Soc.Lond.

    Heterogeneous Adaptive Trajectories of Small Populations on Complex Fitness Landscapes

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    Background Small populations are thought to be adaptively handicapped, not only because they suffer more from deleterious mutations but also because they have limited access to new beneficial mutations, particularly those conferring large benefits. Methodology/Principal Findings Here, we test this widely held conjecture using both simulations and experiments with small and large bacterial populations evolving in either a simple or a complex nutrient environment. Consistent with expectations, we find that small populations are adaptively constrained in the simple environment; however, in the complex environment small populations not only follow more heterogeneous adaptive trajectories, but can also attain higher fitness than the large populations. Large populations are constrained to near deterministic fixation of rare large-benefit mutations. While such determinism speeds adaptation on the smooth adaptive landscape represented by the simple environment, it can limit the ability of large populations from effectively exploring the underlying topography of rugged adaptive landscapes characterized by complex environments. Conclusions Our results show that adaptive constraints often faced by small populations can be circumvented during evolution on rugged adaptive landscapes

    Drift and evolutionary forces: scrutinizing the Newtonian analogy

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    This article analyzes the view of evolutionary theory as a theory of forces. The analogy with Newtonian mechanics has been challenged due to the alleged mismatch between drift and the other evolutionary forces. Since genetic drift has no direction several authors tried to protect its status as a force: denying its lack of directionality, extending the notion of force and looking for a force in physics which also lacks of direction. I analyse these approaches, and although this strategy finally succeeds, this discussion overlooks the crucial point on the debate between causalists and statisticalists: the causal status of evolutionary theory
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