Data from: Temporal variation in antibiotic environments slows down resistance evolution in pathogenic Pseudomonas aeruginosa

Antibiotic resistance is a growing concern to public health. New treatment strategies may alleviate the situation by slowing down the evolution of resistance. Here, we evaluated sequential treatment protocols using two fully independent laboratory-controlled evolution experiments with the human pathogen Pseudomonas aeruginosa PA14 and two pairs of clinically relevant antibiotics (doripenem/ciprofloxacin and cefsulodin/gentamicin). Our results consistently show that the sequential application of two antibiotics decelerates resistance evolution relative to monotherapy. Sequential treatment enhanced population extinction although we applied antibiotics at sub-lethal dosage. In both experiments, we identified an order-effect of the antibiotics used in the sequential protocol, leading to significant variation in the long-term efficacy of the tested protocols. These variations appear to be caused by asymmetric evolutionary constraints, whereby adaptation to one drug slowed down adaptation to the other drug, but not vice versa. An understanding of such asymmetric constraints may help future development of evolutionary robust treatments against infectious disease.

抗生素耐药性已成为日益严峻的公共卫生问题。新型治疗策略或可通过延缓耐药性演化进程缓解这一困境。本研究借助两项完全独立的实验室可控演化实验，以人类致病菌铜绿假单胞菌（Pseudomonas aeruginosa）PA14以及两对临床相关抗生素——多尼培南/环丙沙星（doripenem/ciprofloxacin）与头孢磺啶/庆大霉素（cefsulodin/gentamicin）为模型，评估了序贯治疗方案的效果。研究结果一致显示，相较于单一疗法，两种抗生素的序贯给药可延缓耐药性演化进程。尽管本实验中抗生素给药剂量为亚致死剂量，但序贯治疗仍提升了种群灭绝率。两项实验均发现，序贯治疗方案中抗生素的使用顺序存在效应，导致受试方案的长期药效出现显著差异。此类差异似乎由不对称演化约束所导致：即对一种药物的适应性演化会延缓对另一种药物的适应性演化，反之则不然。对这类不对称演化约束的深入理解，或可助力未来抗感染性疾病的演化稳健型治疗方案开发。