Phage-Antibiotic Synergy (PAS) Study on Novel Bacteria-Phage Pairs and Its Mechanism

Phage-therapy has been proposed as a new therapeutic strategy for many diseases, but one of the major concern is how to increase the phage productivity. Utilization of PAS, a phenomenon whereby sublethal doses of antibiotics stimulate the bacterial production of phages, is a promising solution. Here we report several novel combinations of bacteria and antibiotics, and other stress conditions inducing the PAS effect. Sublethal doses of H2O2 and antibiotics induced PAS in both Gram-positive and Gram-negative bacteria. In addition, in vivo PAS was also observed in C. elegans model system. Increased burst size resulted from increases in phage DNA replication, transcription, translation, and prolonged phage assembly. Upregulation of recA and downregulation of FtsZ were observed under the PAS-inducing condition in E.coli. In recA-deleted E.coli, no significant filamentation was occurred after CPFX treatment, which consequently led to a 3-fold reduction in burst size compared to wild type. However, recA-deficient E.coli also showed weak PAS, demonstrating that recA pathway might not be the only way causing PAS. With our future research, effective phage production could be achieved using PAS in combination with modified E.coli.