Research in: Agricultural & Veterinary Sciences

Bacteria and bacteriophages are engaged in a continuous evolutionary arms race, in which both sides rely on DNA-based defense and counter-defense strategies. Understanding these phage DNA modifications is essential for advancing engineered phage therapy, particularly against multidrug-resistant (MDR) pathogens. This review synthesizes current knowledge on chemically modified phage genomes and highlights how engineered DNA modifications such as those mediated by DpdA and related pathways enable phages to evade bacterial restriction modification systems and CRISPR-Cas immunity. Current study  further examine bacterial countermeasures, including methyltransferase activity and antibiotic resistance determinants, with a focus on Achromobacter species, an emerging MDR pathogen associated with chronic lung infections in cystic fibrosis patients. By integrating evidence from LC-MS/MS, nanopore sequencing and bioinformatic approaches, we outline how these technologies reveal previously uncharacterized phage modifications. This review provides novel insights into how strategically engineered phage DNA can enhance therapeutic stability, broaden host range and overcome bacterial defenses, offering a promising framework for next-generation phage therapy design.