Why doesn't the evolution of antibiotic resistance have a larger fitness cost?

抗生素耐药性是对人类健康和福祉以及粮食生产和动物福利的主要威胁。我们迫切需要更好地理解抗生素耐药性的进化动力学，特别是当抗性选择被移除时会发生什么。耐药性的主要驱动因素是抗生素的持续消费，耐药性的频率在冬季上升，夏季下降，这与抗生素处方的模式相匹配。我们解释这些季节性变化的耐药性流行的概念，具有健身成本的阻力，从而耐药细菌的竞争力或成功比非耐药细菌时，抗生素不存在。然而，健身成本存在的证据是混合的。虽然平均而言抗性是昂贵的，并且大多数抗性突变确实有成本，但超过10%的抗性突变和20%的携带移动的遗传元件的抗性没有可检测的适应性成本或有益（1）。这就产生了两种可能性：要么是我们目前检测成本的方法存在重大缺陷，要么是我们对抗生素耐药性的生态动态进行了复杂的误解。该项目将利用实验室微生物学、数据综合和比较基因组学来探索抗生素耐药性的适应性成本。它将寻求回答：（i）突变真的没有适应度成本吗？(ii)为什么一个移动的遗传元素会有适应度成本？对于前者，有一系列的想法可以解释为什么昂贵的突变似乎是免费的。这些因素包括高度人工化的实验室环境，在某些环境中（但不是所有环境）突变可能是昂贵的，或者某些物种或菌株存在抗性的成本，而不是其他物种或菌株。这个项目的这一部分将使用实验进化和实验室微生物学来区分这些相互竞争的解释。然后，该项目将继续利用大量可公开获得的细菌基因组，将移动的遗传元件的频率和特性与病原体和非病原体生活史特征联系起来。该项目提供了一个很好的机会，了解抗生素耐药性的进化生物学，并接受现代进化微生物学和比较基因组学的世界级培训。该项目将设在阿伯丁大学，由Tom Vogwill博士领导，Tom Vogwill博士是一位进化微生物学家，在抗生素耐药性和微生物进化生态学方面具有专业知识。该项目将由爱丁堡大学的Nick Colegrave教授共同监督，他在进化理论和微生物学方面具有专业知识。参考文献（1）Vogwill，T & MacLean，RC（2015）：抗菌素耐药性的适应性成本的遗传基础：荟萃分析方法。Evol Appl 8：284-295. (2)MacLean，RC & Vogwill，T（2015）：补偿性适应的局限性和病原菌抗生素耐药性的持久性。进化，医学和公共卫生，卷2015，第1期，第4-12页。(3)MacLean，RC & San Millan，A（2015）：Microbial Evolution：Towards Resolving the Plasmid Parkinson.当代生物学25（17），R764-R767。

Antibiotic resistance is a major threat to human health and well-being, as well as food production and animal welfare. There is a pressing need to better our understanding of the evolutionary dynamics of antibiotic resistance, particularly about what happens when selection for resistance is removed. The primary driver of resistance is the ongoing consumption of antibiotics, with the frequency of resistance rising in winter and declining in summer, which matches patterns of antibiotic prescribing. We explain these seasonal shifts in the prevalence of resistance with the concept of resistance having a fitness cost, whereby resistant bacteria are less competitive or successful than non-resistant bacteria when antibiotics are not present. However the evidence for the existence of fitness costs is mixed. Although resistance is costly on average, and most resistance mutations do have a cost, more than 10% of resistance mutations and 20% of resistance carrying mobile genetic elements have either no detectable fitness cost or are beneficial (1). This raises two possibilities: either our current methodologies for detecting costs are significantly flawed, or we have complexly misinterpreted the ecological dynamics of antibiotic resistance. This project will explore the fitness costs of antibiotic resistance using laboratory microbiology, data synthesis, and comparative genomics. It will seek to answer:(i) Can a mutation really have no fitness cost? (ii) Why should a mobile genetic element have a fitness cost?For the former, there are a range of ideas which could explain why a costly mutation might appear to be cost free. These include laboratory environments being highly artificial, mutations could be costly in some environments but not all, or the cost of resistance existing for certain species or strains but not others. This part of the project will us experimental evolution and laboratory microbiology to separate these competing explanations. The project will then go on to take advantage of the huge number of publicly available bacterial genomes to link the frequency and properties of mobile genetic elements to pathogen and non-pathogen life-history traits. The project provides a great opportunity to understand the evolutionary biology of antibiotic resistance and receive world class training in modern evolutionary microbiology and comparative genomics. The project will be based at the University of Aberdeen under the lead supervision of Dr Tom Vogwill, an evolutionary microbiologist with expertise in antibiotic resistance and microbial evolutionary ecology. The project will be co-supervised by Professor Nick Colegrave at the University of Edinburgh, with expertise in evolutionary theory and microbiology. References(1) Vogwill, T & MacLean, RC (2015): The genetic basis of the fitness costs of antimicrobial resistance: a meta-analysis approach. Evol Appl 8: 284-295.(2) MacLean, RC & Vogwill, T (2015): Limits to compensatory adaptation and the persistence of antibiotic resistance in pathogenic bacteria. Evolution, Medicine, and Public Health, Volume 2015, Issue 1, Pages 4-12.(3) MacLean, RC & San Millan, A (2015): Microbial Evolution: Towards Resolving the Plasmid Paradox. Current Biology 25 (17), R764-R767.