Bacterial Defense and Phage Counterdefense: Unraveling the Molecular Basis of Phage Resistance
- 1ITMO University , , Lomonosov St. 9 , ,
- 2Sechenov First Moscow State Medical University (Sechenov University) , , Bolshaya Pirogovskaya St. 2 , ,
Abstract
Phage therapy represents a promising strategy against multidrug-resistant bacteria, but its clinical effectiveness is increasingly compromised by the emergence of phage-resistant traits (PRTs). This resistance develops through multiple interconnected mechanisms that operate at different levels of bacterial defense. At the primary level, mutations in phage receptors, cell surface glycoconjugates (lipopolysaccharide, capsule polysaccharide, exopolysaccharide), outer membrane proteins, drug efflux pumps, and surface layer proteins provide the first line of defense by preventing phage adsorption. These receptors are highly diverse across Gram-negative bacteria, Gram-positive bacteria, and acid-fast bacteria, with PRT being particularly dominant in Gram-negative species. At the secondary level, bacteria deploy sophisticated antiphage defense (APD) systems, including CRISPR-Cas, restriction-modification systems, and abortive infection mechanisms. The recent discovery of over 150 distinct APD systems underscores the remarkable complexity of bacterial immunity. Concurrently, bacteriophages have evolved anti-antiphage defense (AAPD) systems to counter bacterial immunity, establishing a dynamic coevolutionary arms race. This continuous interplay between APD diversification and AAPD counteradaptation drives the rapid emergence of PRT, which threatens the long-term viability of phage therapy. This systematic review examines the molecular basis of phage resistance across diverse bacterial taxa, analyzes the evolutionary and coevolutionary forces shaping APD and AAPD systems, and highlights previously overlooked aspects of phage–bacteria interactions. By integrating these perspectives, we aim to inform strategies for advancing modern phage therapy and guiding future research directions.
Related
- SIR2-mediated filament assembly activates the NLR-like protein Avs5 for bacterial antiviral defense
- Editorial: Advancing plant histopathology: unraveling plant-pathogen interactions and disease resistance mechanisms
- Viral SSB-bound ssDNA activates the bacterial anti-phage defense system DARNA
- DancE: A DNA-Activated Bacterial cGAS-like Enzyme in Antiphage Immune Defense
- Verticillium Wilt Resistance in Solanaceous Crops: Genetic Resources, Grafting-Mediated Systemic Defense, and Implications for Productivity
BibTeX
@article{dutta2026bacterial,
title = {{Bacterial Defense and Phage Counterdefense: Unraveling the Molecular Basis of Phage Resistance}},
author = {Kunal Dutta and Kira M. Velieva and Ekaterina V. Skorb and Sergey Shityakov},
journal = {ACS omega},
year = {2026},
month = sep,
doi = {10.1021/acsomega.6c00530},
url = {https://europepmc.org/article/PMC/PMC13670838},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Bacterial Defense and Phage Counterdefense: Unraveling the Molecular Basis of Phage Resistance
AU - Kunal Dutta
AU - Kira M. Velieva
AU - Ekaterina V. Skorb
AU - Sergey Shityakov
PY - 2026
DA - 2026/09/30
JO - ACS omega
DO - 10.1021/acsomega.6c00530
UR - https://europepmc.org/article/PMC/PMC13670838
AB - Phage therapy represents a promising strategy against multidrug-resistant bacteria, but its clinical effectiveness is increasingly compromised by the emergence of phage-resistant traits (PRTs). This resistance develops through multiple interconnected mechanisms that operate at different levels of bacterial defense. At the primary level, mutations in phage receptors, cell surface glycoconjugates (lipopolysaccharide, capsule polysaccharide, exopolysaccharide), outer membrane proteins, drug efflux pumps, and surface layer proteins provide the first line of defense by preventing phage adsorption. These receptors are highly diverse across Gram-negative bacteria, Gram-positive bacteria, and acid-fast bacteria, with PRT being particularly dominant in Gram-negative species. At the secondary level, bacteria deploy sophisticated antiphage defense (APD) systems, including CRISPR-Cas, restriction-modification systems, and abortive infection mechanisms. The recent discovery of over 150 distinct APD systems underscores the remarkable complexity of bacterial immunity. Concurrently, bacteriophages have evolved anti-antiphage defense (AAPD) systems to counter bacterial immunity, establishing a dynamic coevolutionary arms race. This continuous interplay between APD diversification and AAPD counteradaptation drives the rapid emergence of PRT, which threatens the long-term viability of phage therapy. This systematic review examines the molecular basis of phage resistance across diverse bacterial taxa, analyzes the evolutionary and coevolutionary forces shaping APD and AAPD systems, and highlights previously overlooked aspects of phage–bacteria interactions. By integrating these perspectives, we aim to inform strategies for advancing modern phage therapy and guiding future research directions.
SN - 2470-1343
ER -