JAC Advance Access published online on November 12, 2003
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkg485
© 2003 by The British Society for Antimicrobial Chemotherapy
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Original article
1 Centro Nacional de Microbiología,
Instituto de Salud Carlos III, 28220 Majadahonda, Madrid;
* Corresponding author. E-mail: ruben{at}cib.csic.es.
Received 16 July 2003
; revised 18 September 2003
; accepted 25 September 2003
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 x 107 cfu
of a type 6B, antibiotic-resistant S. pneumoniae clinical
isolate. Results: Animals challenged with 5 x 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 <106 cfu/mL over
time and ultimately became undetectable. Interestingly, a synergic
effect in vivo was observed with the combined use
of 2.5 µg each of Cpl-1 and Pal. 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.
Keywords: enzybiotics, pneumococcus, phage, lytic enzymes
Phage lytic enzymes as therapy for antibiotic-resistant Streptococcus pneumoniae infection in a murine
sepsis model
2 Departamento de Microbiología
Molecular, Centro de Investigaciones Biológicas, CSIC,
Ramiro de Maeztu 9, 28040 Madrid, Spain
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