Temperate phages increase antibiotic effectiveness in aCaenorhabditis elegansinfection model

Abstract

The bactericidal nature of obligately lytic bacterial viruses (phages) is of increasing interest for the treatment of drug-resistant bacterial infections, either administered alone or in combination with antibiotics. In contrast, temperate phages are largely ignored in a therapeutic context due to their ability to lie dormant within the bacterial host. However, these phages often undergo a lytic cycle. Furthermore, even in their dormant state their carriage can be a considerable burden to the bacterium — most famously by their ability to switch to lytic replication in response to environmental triggers, such as antibiotics, that stress the bacterial host. Recent reports of antibiotics synergizing uniquely with temperate phages in vitro, termed 'temperate phage antibiotic synergy' (tPAS), present a potentially scalable opportunity to make use of these abundant entities for the treatment of bacterial infections. Here we employCaenorhabditis elegansas a robustin vivoanimal model for testing the efficacy of temperate phages as adjuvants to antibiotics. In vivo, the antibiotic ciprofloxacin can abolish dormancy of temperate phage Hali - infecting a ciprofloxacin resistantPseudomonas aeruginosaclinical strain - while in the absence of the antibiotic dormancy events explain 60% of the bacterial survivors. The Phage Hali-ciprofloxacin pairing increased the lifespan ofP. aeruginosainfected 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 normally prescribed. Our work establishesC. elegansas a suitable model for studying the in vivo efficacy of tPAS and is the firstin vivodemonstration of this synergy, greatly expanding the therapeutic potential of temperate phages.