Loss of restriction-modification methyltransferases drives persistence to fluoroquinolones in Pseudomonas aeruginosa
- 1University of Exeter
Abstract
The resurgence of phage therapy has renewed interest in the interplay between phage resistance and antibiotic susceptibility and has stimulated research in the emergent field of non-canonical cellular functions carried out by defence systems. Yet it remains largely unknown whether intracellular antiphage defence systems influence bacterial physiology, resistance or persistence to antibiotics. Here we discovered that besides its canonical antiphage defence function, the type I restriction modification (RM) system profoundly affects the physiology of the opportunistic pathogen Pseudomonas aeruginosa. Deletion of the type I RM methyltransferase HsdM reduces the size of the bacterial nucleoid and delays DNA replication initiation and exit from lag phase in P. aeruginosa PAO1. Crucially, P. aeruginosa strains isolated from patients with cystic fibrosis (CF) and lacking the RM type I system also display slower growth compared to strains isolated from other sites of infections and encoding this system. Deletion of HsdM selectively increases the levels of persisters that survive treatment with fluoroquinolones by displaying enhanced SOS response but without acquiring resistance. Importantly, we measured elevated persistence to fluoroquinolones also in P. aeruginosa CF isolates lacking the type I RM system, providing a functional link between RM systems, slow growth and persistence to fluoroquinolones. Together these findings open a new way of approaching bacterial susceptibility to antibiotics, bringing antiphage defence systems in a forward-facing position in this field.
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BibTeX
@misc{micaletto2026loss,
title = {{Loss of restriction-modification methyltransferases drives persistence to fluoroquinolones in Pseudomonas aeruginosa}},
author = {M. Micaletto and N. O. Gomez and A. Olina and A. Agapov and U. Lapinska and M. Preusse and M. Garcia Castillo and C. Hacker and R. Canton and S. van Houte and S. Haussler and E. R. Westra and Multi-Defence Consortium and ERADIAMR Consortium and S. Pagliara},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.26.754597},
url = {https://www.biorxiv.org/content/10.64898/2026.09.26.754597v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Loss of restriction-modification methyltransferases drives persistence to fluoroquinolones in Pseudomonas aeruginosa
AU - M. Micaletto
AU - N. O. Gomez
AU - A. Olina
AU - A. Agapov
AU - U. Lapinska
AU - M. Preusse
AU - M. Garcia Castillo
AU - C. Hacker
AU - R. Canton
AU - S. van Houte
AU - S. Haussler
AU - E. R. Westra
AU - Multi-Defence Consortium
AU - ERADIAMR Consortium
AU - S. Pagliara
PY - 2026
DA - 2026/09/26
PB - bioRxiv
DO - 10.64898/2026.09.26.754597
UR - https://www.biorxiv.org/content/10.64898/2026.09.26.754597v1
AB - The resurgence of phage therapy has renewed interest in the interplay between phage resistance and antibiotic susceptibility and has stimulated research in the emergent field of non-canonical cellular functions carried out by defence systems. Yet it remains largely unknown whether intracellular antiphage defence systems influence bacterial physiology, resistance or persistence to antibiotics. Here we discovered that besides its canonical antiphage defence function, the type I restriction modification (RM) system profoundly affects the physiology of the opportunistic pathogen Pseudomonas aeruginosa. Deletion of the type I RM methyltransferase HsdM reduces the size of the bacterial nucleoid and delays DNA replication initiation and exit from lag phase in P. aeruginosa PAO1. Crucially, P. aeruginosa strains isolated from patients with cystic fibrosis (CF) and lacking the RM type I system also display slower growth compared to strains isolated from other sites of infections and encoding this system. Deletion of HsdM selectively increases the levels of persisters that survive treatment with fluoroquinolones by displaying enhanced SOS response but without acquiring resistance. Importantly, we measured elevated persistence to fluoroquinolones also in P. aeruginosa CF isolates lacking the type I RM system, providing a functional link between RM systems, slow growth and persistence to fluoroquinolones. Together these findings open a new way of approaching bacterial susceptibility to antibiotics, bringing antiphage defence systems in a forward-facing position in this field.
ER -