The widespread use of antibiotics promotes the evolution and dissemination of resistance and tolerance mechanisms. To assess the relevance of tolerance and its implications for resistance development, we used in vitro evolution and analyzed in-patient microevolution of Pseudomonas aeruginosa, an important human pathogen causing acute and chronic infections. We show that the development of tolerance precedes and promotes the acquisition of resistance in vitro and we present evidence that similar processes shape antibiotic exposure in human patients. Our data suggest that during chronic infections, P. aeruginosa first acquires moderate drug tolerance before following distinct evolutionary trajectories that lead to high-level multi-drug tolerance or to antibiotic resistance. Our studies propose that the development of antibiotic tolerance predisposes bacteria for the acquisition of resistance at early stages of infection and that both mechanisms independently promote bacterial survival during antibiotic treatment at later stages of chronic infections.

中文翻译：

---

铜绿假单胞菌感染的抗生素耐受性演变影响耐药性发展。

抗生素的广泛使用促进了耐药性和耐受性机制的进化和传播。为了评估耐受性的相关性及其对耐药性发展的影响，我们使用了体外进化并分析了铜绿假单胞菌（Pseudomonas aeruginosa）的住院微演变，铜绿假单胞菌是引起急性和慢性感染的重要人类病原体。我们表明耐受性的发展先于并促进了体外抗药性的获得，并且我们提供了证据表明相似的过程会影响人类患者体内的抗生素暴露。我们的数据表明，在慢性感染期间，铜绿假单胞菌首先获得中等的药物耐受性，然后才遵循导致高水平的多重药物耐受性或抗生素耐药性的独特进化轨迹。