Phenotypic resistance to phage infection through capsule expression shutdown in Klebsiella pneumoniae

Capsule loss is a major mechanism by which bacteria evade phage infection. This process has traditionally been attributed to mutations in capsule biosynthesis genes. Here, we investigated phage resistance in Klebsiella pneumoniae, a medically relevant encapsulated bacterium. Phage infection rapidly selected for resistant acapsular cells. As expected, transcriptomic analysis revealed a marked downregulation of capsule biosynthesis genes. However, full genome sequencing showed that capsule loss occurred without evidence of mutations, and acapsular phage-resistant cells were able to rapidly restore their capsule once phage pressure was removed. These findings highlight that phage-driven selective pressure can act on non-heritable variation in gene expression, providing a faster and more flexible resistance mechanism compared to the traditional mutation-selection process. IMPORTANCEBacteriophages are increasingly considered as alternatives or complements to antibiotics, particularly against multidrug-resistant pathogens like Klebsiella pneumoniae. A key barrier to effective phage therapy is the rapid emergence of bacterial resistance. Capsule loss is a common resistance mechanism, traditionally linked to genetic mutations. Here, we show that K. pneumoniae can evade phage infection through reversible, non-mutational downregulation of capsule biosynthesis. This phenotypic adaptation allows rapid resistance development without compromising long-term fitness. Our findings reveal a flexible, non-genetic resistance strategy that may limit the durability of phage therapy and should be considered in future phage treatment designs.