Genetic Polymorphism Drives Susceptibility Between Bacteria and Bacteriophages

Area of Science:

• Microbiology
• Genetics
• Evolutionary Biology

Background:

• Phage therapy is a promising alternative for treating antibiotic-resistant bacteria.
• Bacteria rapidly develop resistance to lytic phages, limiting therapeutic efficacy.
• Understanding the mechanisms of phage resistance is crucial for optimizing phage therapy.

Purpose of the Study:

• To investigate the mechanisms of bacterial resistance to phage therapy using *Staphylococcus aureus* and its lytic phage LQ7.
• To identify genetic factors contributing to phage resistance and explore strategies to overcome it.

Main Methods:

• Isolation and characterization of a phage-resistant *Staphylococcus aureus* mutant (R1-3-1).
• Experimental evolution of the lytic phage LQ7 against the resistant mutant.
• Whole-genome sequencing (NGS) of bacterial strains and phages.
• Analysis of genetic mutations and polymorphisms.
• Assessment of bacterial sensitivity to phage therapy in the presence of chloramphenicol (CHL).

Main Results:

• A phage-resistant mutant (R1-3-1) was isolated, and evolved phages were found to infect it.
• While few mutations were observed, widespread minor allele genetic polymorphisms were present in both bacteria and phages.
• Specific polymorphisms in R1-3-1's metabolic pathways were targeted by chloramphenicol (CHL), restoring phage sensitivity.
• Combined CHL and evolved phage treatment showed the least resistance development in *Staphylococcus aureus* AB91118.

Conclusions:

• Minor allele genetic polymorphism represents a novel mechanism driving phage-host co-evolution.
• This polymorphism allows for rapid adaptation to selective pressures between phages and bacteria.
• Combined antibiotic and phage therapy may offer a more effective strategy against resistant bacterial infections.