On the rapidity of antibiotic resistance evolution facilitated by a concentration gradient
On the rapidity of antibiotic resistance evolution facilitated by a concentration gradient
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DOI：
10.1073/pnas.1117716109
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发表时间：
2012-07-03
影响因子：
11.1
通讯作者：
Hwa, Terence
中科院分区：
文献类型：
--
作者：
Hermsen, Rutger;Deris, J. Barrett;Hwa, Terence
对多种抗生素具有耐药性的细菌菌株的迅速出现正在构成日益严重的公共卫生风险。然而，人们对耐药性快速演变背后的机制知之甚少。细菌遇到抗生素药物的环境的异质性可能起着重要作用。例如，在高度区隔的人体中，药物水平在不同器官和组织之间可能有很大差异。有人提出，这可能有助于抗性突变体的选择，最近的实验也支持这一点。为了研究空间异质性在耐药性进化中的作用，我们提出了一个定量模型，描述了一个被细分为具有不同抗生素浓度的相对孤立的隔间的环境，在这个环境中，细菌在增殖、迁移、突变和死亡的随机过程中进化。分析和数值结果表明，浓度梯度可以促进一种适应模式，这在均匀环境中是不可能的。它允许耐药突变体通过侵入具有较高药物浓度的隔室来逃避竞争并绕过缓慢的固定过程，而耐药较少的菌株无法在那里生存。这一过程的速度随着生长速度对抗生素浓度的敏感性而急剧增加，我们认为抗生素浓度是通用的。在相同的环境中，相似的适应率要求每个前向突变具有较高的选择系数（5>.1）。如果异质性比线性梯度更复杂，也会发生类似的过程。该模型也适用于其他涉及环境异质性和范围扩展的自适应过程。
The rapid emergence of bacterial strains resistant to multiple antibiotics is posing a growing public health risk. The mechanisms underlying the rapid evolution of drug resistance are, however, poorly understood. The heterogeneity of the environments in which bacteria encounter antibiotic drugs could play an important role. E.g., in the highly compartmentalized human body, drug levels can vary substantially between different organs and tissues. It has been proposed that this could facilitate the selection of resistant mutants, and recent experiments support this. To study the role of spatial heterogeneity in the evolution of drug resistance, we present a quantitative model describing an environment subdivided into relatively isolated compartments with various antibiotic concentrations, in which bacteria evolve under the stochastic processes of proliferation, migration, mutation and death. Analytical and numerical results demonstrate that concentration gradients can foster a mode of adaptation that is impossible in uniform environments. It allows resistant mutants to evade competition and circumvent the slow process of fixation by invading compartments with higher drug concentrations, where less resistant strains cannot subsist. The speed of this process increases sharply with the sensitivity of the growth rate to the antibiotic concentration, which we argue to be generic. Comparable adaptation rates in uniform environments would require a high selection coefficient (s > 0.1) for each forward mutation. Similar processes can occur if the heterogeneity is more complex than just a linear gradient. The model may also be applicable to other adaptive processes involving environmental heterogeneity and range expansion.