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7 p.-5 fig., Objectives: Phage-coded lysins, i.e. murein hydrolases, are enzymes that destroy the cell wall of bacteria. A rapid killing of Streptococcus pneumoniae in the nasopharynx of mice has been described recently using a phage-coded murein hydrolase (enzybiotic). The in vivo effects of a dose-ranging treatment, using either of the phage-coded lytic enzymes Cpl-1 lysozyme or the Pal amidase, have been investigated here in a murine sepsis model., Methods: Purified Pal amidase and/or Cpl-1 lysozyme were used alone or in combination. These enzymes were injected intraperitoneally at different times after challenge with 5 × 107 cfu of a type 6B, antibiotic-resistant S. pneumoniae clinical isolate., Results: Animals challenged with 5 × 107 cfu of this strain alone died within 72 h, whereas a single intraperitoneal injection of Cpl-1 or Pal (200 µg; 1100 U) administered 1 h after the bacterial challenge was sufficient to effectively protect the mice, according to unpaired t-test (P < 0.0001). Bacteraemia in unprotected mice reached colony counts >107 cfu/mL, whereas the mean colony count in lysin-protected animals was, Conclusions: Our findings suggest strongly that phage lysins protect animals from bacteraemia and death. Moreover, the simultaneous attack of the pneumococcal peptidoglycan by a lysozyme and an amidase leads to a remarkable effect through enhanced destruction of the bacterial cell wall. The benefits of therapy with enzybiotics against pneumococcus reported here might warrant the examination of alternative strategies for the treatment of diseases caused by clinically relevant pathogens., This work was supported by grants from the Dirección General de Investigación Científica y Técnica (BCM2000-1002) and from Redes Temáticas de Investigación Cooperativa (G03/103 and C03/14) (Ministerio de Sanidad y Consumo).