Decoupling the molecular versatility of aminoglycosides via drug or target modification enables community-wide antiphage defense

The ongoing arms race between bacteria and phages has forced bacteria to evolve a sophisticated set of antiphage defense mechanisms that constitute the bacterial immune system. In our previous study, we highlighted the antiphage properties of aminoglycoside antibiotics, which are naturally secreted by Streptomyces. Successful inhibition of phage infection was achieved by addition of pure compounds and supernatants from a natural producer strain highlighting the potential for community-wide antiphage defense. However, given the dual functionality of these compounds, neighboring bacterial cells require resistance to the antibacterial activity of aminoglycosides to benefit from the protection they confer against phages. In this study, we demonstrated the successful uncoupling of antiphage and antibacterial properties via different aminoglycoside-resistance mechanisms encompassing drug and target site modifications. Furthermore, we confirmed the antiphage impact of aminoglycosides in a community context by co-culturing phage-susceptible, apramycin-resistant S. venezuelae with the apramycin-producing strain Streptoalloteichus tenebrarius. Given the prevalence of aminoglycoside resistance among natural bacterial isolates that allow functional uncoupling of these compounds, this study highlights the ecological relevance of chemical defense via aminoglycosides at the community level.