Bacteriophage (phage) therapy is a promising anti-infective option to combat antimicrobial resistance. However, the clinical utilization of phage therapy has been severely compromised by the potential emergence of phage resistance. Although certain phage resistance mechanisms can restore bacterial susceptibility to certain antibiotics, a lack of knowledge of phage resistance mechanisms hinders optimal use of phages and their combination with antibiotics. Genome-wide transposon screening was performed with a mutant library of MKP103 to identify phage pKMKP103_1-resistant mutants. Phage-resistant phenotypes were evaluated by time-kill kinetics and efficiency of plating assays. Phage resistance mechanisms were investigated with adsorption, one-step growth, and mutation frequency assays. Antibiotic susceptibility was determined with broth microdilution and population analysis profiles. We observed a repertoire of phage resistance mechanisms in , such as disruption of phage binding (::Tn and ::Tn), extension of the phage latent period (::Tn and ::Tn), and increased mutation frequency (::Tn and ::Tn). Notably, in contrast to the prevailing view that phage resistance re-sensitizes antibiotic-resistant bacteria, we observed a bidirectional steering effect on bacterial antibiotic susceptibility. Specifically, ::Tn increased susceptibility to colistin while ::Tn and ::Tn increased resistance to rifampicin and colistin. Our findings demonstrate that employs multiple strategies to overcome phage infection, which may result in enhanced or reduced antibiotic susceptibility. Mechanism-guided phage steering should be incorporated into phage therapy to better inform clinical decisions on phage-antibiotic combinations.

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肺炎克雷伯菌的噬菌体耐药性和影响抗生素敏感性的双向效应

噬菌体（噬菌体）疗法是对抗抗菌素耐药性的一种有前途的抗感染选择。然而，噬菌体治疗的临床应用因噬菌体耐药性的潜在出现而受到严重影响。尽管某些噬菌体抗性机制可以恢复细菌对某些抗生素的敏感性，但缺乏对噬菌体抗性机制的了解阻碍了噬菌体及其与抗生素的组合的最佳使用。使用 MKP103 突变体库进行全基因组转座子筛选，以鉴定噬菌体 pKMKP103_1 抗性突变体。通过时间杀死动力学和平板测定的效率来评估噬菌体抗性表型。通过吸附、一步生长和突变频率测定研究了噬菌体抗性机制。通过微量肉汤稀释和群体分析曲线确定抗生素敏感性。我们观察到噬菌体抗性机制的全部内容，例如噬菌体结合的破坏（::Tn和::Tn）、噬菌体潜伏期的延长（::Tn和::Tn）以及突变频率的增加（::Tn）和::Tn)。值得注意的是，与噬菌体抗性使抗生素抗性细菌重新敏感的普遍观点相反，我们观察到细菌抗生素敏感性的双向转向效应。具体而言，::Tn 增加对粘菌素的敏感性，而 ::Tn 和 ::Tn 增加对利福平和粘菌素的耐药性。我们的研究结果表明，采用多种策略来克服噬菌体感染，这可能会导致抗生素敏感性增强或降低。应将机制引导的噬菌体转向纳入噬菌体治疗中，以便更好地为噬菌体-抗生素组合的临床决策提供信息。