Phage Intolerance Impacts Antibiotic Susceptibility and Virulence in Staphylococcus aureus

Area of Science:

• Microbiology
• Bacteriology
• Genetics

Background:

• Phage therapy offers a promising alternative to antibiotics due to rising antibiotic resistance.
• Bacterial resistance to phages can emerge, potentially limiting therapeutic success.
• In Staphylococcus aureus, phage resistance is often linked to modifications in cell wall-associated teichoic acids (WTA).

Purpose of the Study:

• To identify genetic factors contributing to phage resistance in Staphylococcus aureus.
• To investigate the impact of phage resistance mutations on bacterial virulence and antibiotic susceptibility.

Main Methods:

• Exposure of Staphylococcus aureus to lytic K-type myoviruses (phage K, ϕIPLA-RODI, Stab21) to generate resistant mutants.
• Genomic analysis of phage-resistant mutants to identify mutations.
• Assessment of virulence in Galleria mellonella models and evaluation of antibiotic susceptibility.

Main Results:

• One-third of phage-resistant mutants had mutations in known cell-wall genes (femA, tagO).
• The remaining mutants exhibited mutations in previously unassociated pathways, including nucleoside catabolism (deoC1), polyamine import (potA, potB), and RNA helicase (cshA).
• Mutations in WTA synthesis increased beta-lactam sensitivity and reduced virulence, while cshA mutations increased both virulence and beta-lactam susceptibility.

Conclusions:

• Reduced phage susceptibility in S. aureus can stem from mutations in central metabolic processes, not solely receptor modifications.
• Phage resistance can lead to unpredictable changes in antibiotic susceptibility and bacterial virulence.
• Evolutionary trade-offs must be evaluated prior to the clinical application of phage therapy.