Bacteriophage Therapy of Experimental Bubonic Plague in Mice

The emergence of multidrug-resistant strains of Yersinia pestis may result in epidemics of untreatable bubonic and pneumonic plague and requires urgent development of alternative therapeutics. The purpose of this work was to test plague diagnostic bacteriophages as a potential therapy against experimental bubonic plague. Purified phages φA1122 and L-413C remained stable at least for 2 years in phosphate-buffered saline with gelatin at 4°C. None of these two phages showed a cytotoxic effect on mouse macrophages, as well as human monocytes and hepatocytes. The φA1122 phage also demonstrated a lack of acute toxicity to mice. After single intraperitoneal (IP) or intramuscular (IM) administration to mice in a dose of 5 × 109 PFU (plaque-forming unit), the phage was detected in blood, liver, and spleen during 5 days of observation in one log higher concentrations when using IP route (vs. IM route). Pharmacodynamics tests showed the propagation of φA1122 in the liver and spleen of mice infected with Y. pestis. Neither φA1122 and L-413C suspensions nor the phage particles preadsorbed to Y. pestis cells demonstrated any bactericidal effect inside mouse macrophages. However, a IP administration of φA1122 (5 × 109 live phage particles) provided 40% protection of BALB/c mice against 1,000 LD50 of Y. pestis CO92 and extended mean time to death of nonsurvivors by 84%. Our data showed that φA1122 bacteriophage is a promising alternative therapy against multidrug-resistant plague.