Staphylococcus aureus is a major human pathogen that, after developing resistance to methicillin, has clinically displayed decreased sensitivity to vancomycin, the drug of last resort. Vancomycin-Intermediate S. aureus (VISA) results in cell wall modifications, which include altered cross-linking and cell wall charge and increased cell wall thickness. As VISA is associated with treatment failure, we explored the activity of phage cocktails or individual phages against this pathogen.
The clinical VISA isolate PC3 was serially passed with or without vancomycin in order to alleviate or exacerbate VISA-associated phenotypes in a shared genetic backgrounds. Changes in the Minimum Inhibitory Concentration (MIC) and cell wall thickness were documented for vancomycin -free or –maintained strains. While the vancomycin-free strain was highly susceptible to phage infection, exposure to vancomycin resulted in a concomitant decrease in phage sensitivity to all phages, evident through phage titers, drop tests, and killing assays. Adsorption assays revealed that phage was indeed removed from the surrounding media, and phage titers decreased by >3 log from initial titers after 24 hours. While phage receptors remain accessible on the cell surface of VISA, Hershey-Chase experiments are ongoing in order to elucidate at which point phage infection is impaired. This phenomenon is specific to VISA and not observed for vanA-mediated vancomycin resistance in Vancomycin Resistance S. aureus (VRSA).
Bacteriophage therapy has a lot to offer in wake of the ongoing antibiotic resistance crisis. However, it is important to understand the circumstances for which phage therapy is a viable option and how antibiotic resistance mechanisms may alter phage efficacy. This is the first study investigating the influence of antibiotic-induced cell-wall changes on phage infectivity in S. aureus and holds clinical implications for the future of S. aureus phage therapy.