Bacteriophage infection drives loss of β-lactam resistance in methicillin-resistant Staphylococcus aureus

Bacteriophage (phage) therapy has been proposed as a means to combat drug-resistant bacterial pathogens. Infection by phage can select for mutations in bacterial populations that confer resistance against phage infection. However, resistance against phage can yield evolutionary trade-offs of biomedical use. Here we report the discovery of staphylococcal phages that cause different strains of methicillin-resistant Staphylococcus aureus (MRSA) to become sensitized to β-lactams, a class of antibiotics against which MRSA is typically highly resistant. MRSA cells that survive infection by these phages display significant reductions in minimal inhibitory concentration against different β-lactams compared to uninfected bacteria. Phage-treated MRSA further exhibited attenuated virulence phenotypes in the form of reduced hemolysis and clumping. Sequencing analysis revealed that the different MRSA strains evolved unique genetic profiles during infection. These results suggest complex evolutionary trajectories in MRSA during phage predation and open up new possibilities to reduce drug resistance and virulence in MRSA infections.