Affiliation:
1. The Laboratory of Bacterial Pathogenesis and Immunology, The Rockefeller University, 1230 York Ave., Box 172, New York, New York 10065
Abstract
ABSTRACT
Staphylococcus aureus
is the causative agent of several serious infectious diseases. The emergence of antibiotic-resistant
S. aureus
strains has resulted in significant treatment difficulties, intensifying the need for new antimicrobial agents. Toward this end, we have developed a novel chimeric bacteriophage (phage) lysin that is active against staphylococci, including methicillin-resistant
S. aureus
(MRSA). The chimeric lysin (called ClyS) was obtained by fusing the N-terminal catalytic domain of the
S. aureus
Twort phage lysin with the C-terminal cell wall-targeting domain from another
S. aureus
phage lysin (phiNM3), which displayed
Staphylococcus
-specific binding. ClyS was expressed in
Escherichia coli
, and the purified protein lysed MRSA, vancomycin-intermediate strains of
S. aureus
(VISA), and methicillin-sensitive (MSSA) strains of
S. aureus in vitro
. In a mouse nasal decolonization model, a 2-log reduction in the viability of MRSA cells was seen 1 h following a single treatment with ClyS. One intraperitoneal dose of ClyS also protected against death by MRSA in a mouse septicemia model. ClyS showed a typical pattern of synergistic interactions with both vancomycin and oxacillin
in vitro
. More importantly, ClyS and oxacillin at doses that were not protective individually protected synergistically against MRSA septic death in a mouse model. These results strongly support the development of ClyS as an attractive addition to the current treatment options of multidrug-resistant
S. aureus
infections and would allow for the reinstatement of antibiotics shelved because of mounting resistance.
Publisher
American Society for Microbiology
Subject
Infectious Diseases,Pharmacology (medical),Pharmacology
Cited by
185 articles.
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