Resistance evolution against phage combinations depends on the timing and order of exposure

Globally rising rates of antibiotic resistance have renewed interest in phage therapy where combinations of phages have been successfully used to treat multidrug resistant infections. To optimise phage therapy, we first need to understand how bacteria evolve resistance against combinations of multiple phages. Here we use simple laboratory experiments and genome sequencing to show that the timing and order of phage exposure determine the strength, cost and mutational basis of resistance evolution in the opportunistic pathogen Pseudomonas aeruginosa. These findings suggest that phage combinations can be optimised to limit the emergence and persistence of resistance, thereby promoting the long-term usefulness of phage therapy.

全球范围内抗生素耐药性发生率持续攀升，使得噬菌体疗法再度受到学界关注——此前噬菌体组合疗法已成功用于治疗多重耐药感染。为优化噬菌体疗法，我们首先需要阐明细菌如何针对多种噬菌体组合演化出耐药性。本研究通过简易实验室实验与基因组测序证实，噬菌体暴露的时机与施加顺序，决定了机会致病菌铜绿假单胞菌（Pseudomonas aeruginosa）耐药性演化的强度、适合度代价及突变基础。上述研究结果表明，可通过优化噬菌体组合方案以限制耐药性的出现与存续，进而提升噬菌体疗法的长期实用价值。