Temperate phages increase antibiotic effectiveness in a <i>Caenorhabditis elegans</i> infection model

ABSTRACT The bactericidal nature of obligately lytic bacterial viruses (phages) is of increasing interest for the treatment of drug-resistant bacterial infections, often alongside antibiotics. By contrast, temperate phages are largely ignored due to their ability to lie dormant within the bacterial host. However, these phages often undergo a lytic cycle. Furthermore, in their dormant state, they switch to lytic replication in response to triggers, such as antibiotics, that stress the bacterial host. Recent reports of antibiotics synergizing with temperate phages in vitro , termed “temperate phage-antibiotic synergy” (tPAS), present a potentially scalable opportunity to make use of these abundant entities in therapy. Here, we employ Caenorhabditis elegans as a model to test the efficacy of temperate phages. In vivo , temperate phage Hali alone results in 60% dormancy in the bacterial survivors. However, the antibiotic ciprofloxacin can abolish dormancy of the phage—even in a ciprofloxacin-resistant Pseudomonas aeruginosa clinical strain. The phage Hali-ciprofloxacin pairing increased the lifespan of P. aeruginosa -infected worms to that of the uninfected control, at doses where neither the phage nor the antibiotic had any effect alone. Complete rescue was also observed in worms infected with a phage-carrying strain treated with the otherwise ineffective antibiotic, supporting that the phage—even in its dormant form—can greatly enhance antibiotic effectiveness. This illustrates potential “accidental” phage therapy when antibiotics are prescribed. As the first in vivo demonstration of tPAS, our work establishes C. elegans as a model for studying it, greatly expanding the therapeutic potential of temperate phages. IMPORTANCE Bacterial viruses (phages), which can go dormant in their host, are not considered suitable for phage therapy. Building on prior work showing antibiotics synergize with these phages by preventing dormancy, we test the ability of temperate phages—in combination with antibiotics—in an animal model of infection. Not only were the combinations extremely effective at doses that would do nothing alone, even when the bacterium was resistant to the antibiotics—but we also found that whether the dormant phage pre-existed (as it does in about 75% of bacteria) or not determined the success of antibiotic treatments, suggesting many antibiotic treatments are already a form of “accidental” phage therapy.

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