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率的不断上升，使得噬菌体疗法重新引起了人们的关注，其中噬菌体组合的成功应用已被用于治疗多重耐药性感染。为了优化噬菌体疗法，我们首先需要理解细菌如何对多种噬菌体的组合产生耐药性。在本研究中，我们通过简单的实验室实验和基因组测序表明，噬菌体暴露的时机和顺序决定了条件致病菌铜绿假单胞菌耐药性进化的强度、代价和突变基础。这些发现表明，噬菌体组合可以通过优化来限制耐药性的出现和持续，从而促进噬菌体疗法的长期应用价值。