Loss of restriction-modification methyltransferases drives persistence to fluoroquinolones in Pseudomonas aeruginosa

Recent interest in phage therapy has reignited research into the relationship between phage resistance and antibiotic susceptibility, leading to the exploration of non-canonical cellular functions by defense systems. However, it remains unclear if intracellular antiphage defense systems impact bacterial physiology, resistance, or persistence to antibiotics.

In this study, researchers found that the type I restriction modification (RM) system, which typically functions to protect bacteria from phages, also significantly influences the physiology of the opportunistic pathogen Pseudomonas aeruginosa. Deleting the type I RM methyltransferase HsdM leads to a smaller bacterial nucleoid, delayed DNA replication initiation, and a longer lag phase in P. aeruginosa PAO1.

Moreover, CF patients' P. aeruginosa strains lacking the RM type I system exhibit slower growth compared to those isolated from other infection sites and encoding this system. Deleting HsdM selectively increases the levels of persisters that survive fluoroquinolone treatment, displaying an enhanced SOS response without acquiring resistance.

Crucially, researchers measured increased persistence to fluoroquinolones in CF isolates lacking the type I RM system, establishing a functional link between RM systems, slow growth, and persistence to fluoroquinolones.

These findings suggest that antiphage defense systems could play a new and significant role in understanding bacterial susceptibility to antibiotics, placing these systems at the forefront of the field.