Abstract
We used a mouse model to establish safety and efficacy of a bacteriophage cocktail, ShigActive™, in reducing fecal Shigella counts after oral challenge with a susceptible strain. Groups of inbred C57BL/6J mice challenged with Shigella sonnei strain S43-NalAcR were treated with a phage cocktail (ShigActive™) composed of 5 lytic Shigella bacteriophages and ampicillin. The treatments were administered (i) 1 h after, (ii) 3 h after, (iii) 1 h before and after, and (iv) 1 h before bacterial challenge. The treatment regimens elicited a 10- to 100-fold reduction in the CFU's of the challenge strain in fecal and cecum specimens compared to untreated control mice, (P < 0.05). ShigActiveTM treatment was at least as effective as treatment with ampicillin but had a significantly less impact on the gut microbiota. Long-term safety studies did not identify any side effects or distortions in overall gut microbiota associated with bacteriophage administration. Shigella phages may be therapeutically effective in a “classical phage therapy” approach, at least during the early stages after Shigella ingestion. Oral prophylactic “phagebiotic” administration of lytic bacteriophages may help to maintain a healthy gut microbiota by killing specifically targeted bacterial pathogens in the GI tract, without deleterious side effects and without altering the normal gut microbiota.
Highlights
Bacterial diseases of the gastrointestinal (GI) tract continue to be a major worldwide cause of human morbidity and mortality
Short-term efficacy studies During preliminary short-term efficacy studies, we found that 72 h after a Shigella inoculum of 1.2 £ 108 colony-forming units (CFU)/mouse a 10:1 phage: Shigella concentration completely eliminated bacteria in stool samples, cecal and small intestinal contents
In vitro lytic activity of the phage preparation The ability of ShigActiveTM to lyse Shigella strains in vitro was evaluated against a collection of 65 strains of Shigella spp isolated from clinical cases of shigellosis in various countries and S. sonnei strain 9290 obtained from the ATCC
Summary
Bacterial diseases of the gastrointestinal (GI) tract continue to be a major worldwide cause of human morbidity and mortality. One possible approach is to use bacteriophages capable of killing Shigella in the GI tract during the early stages of shigellosis (i.e., a “classical phage therapy” approach) and/or before Shigella colonize the GI tract and cause disease (i.e., a prophylactic “phagebiotic” approach). Bacteriophages are bacterial viruses that are arguably the oldest and most ubiquitous organisms on Earth.[8] In contrast to antibiotics, lytic phages are fairly specific, usually targeting only a subgroup of strains within one bacterial species or across closely-related species Their remarkable antibacterial activity prompted the use of “phage therapy” for treating various bacterial human diseases. Double dosing regimen (i.e., 1 h before and 1 h after challenge) appeared to be the most effective among the treatment regimens examined: there were 26 CFU/pellet
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