PDF(Pubmed)
Abstract：
The rational design of the antibiotic treatment of bacterial infections employs these drugs to reach concentrations that exceed the minimum needed to prevent the replication of the target bacteria. However, within a treated patient, spatial and physiological heterogeneity promotes antibiotic gradients such that the concentration of antibiotics at specific sites is below the minimum needed to inhibit bacterial growth. Here, we investigate the effects of sub-inhibitory antibiotic concentrations on three parameters central to bacterial infection and the success of antibiotic treatment, using in vitro experiments with Staphylococcus aureus and mathematical-computer simulation models. Our results, using drugs of six different classes, demonstrate that exposure to sub-inhibitory antibiotic concentrations not only alters the dynamics of bacterial growth but also increases the mutation rate to antibiotic resistance and decreases the rate of production of persister cells thereby reducing the persistence level. Understanding this trade-off between mutation rates and persistence levels resulting from sub-inhibitory antibiotic exposure is crucial for optimizing, and mitigating the failure of, antibiotic therapy.
摘要：
细菌感染的抗生素治疗的合理设计使用这些药物以达到超过防止目标细菌复制所需的最小值的浓度。然而,在接受治疗的患者中，空间和生理异质性促进抗生素梯度,使得特定部位的抗生素浓度低于抑制细菌生长所需的最小值。这里,我们研究了亚抑制性抗生素浓度对细菌感染和抗生素治疗成功的三个参数的影响，使用金黄色葡萄球菌和数学计算机模拟模型的体外实验。我们的结果,使用六种不同类别的药物，证明暴露于亚抑制性抗生素浓度不仅会改变细菌生长的动力学，还会增加对抗生素抗性的突变率，并降低持久性细胞的产生率，从而降低持久性水平。了解亚抑制性抗生素暴露导致的突变率和持久性水平之间的权衡对于优化至关重要，减轻失败，抗生素治疗。
