Synergism between a novel chimeric lysin and oxacillin protects against infection by methicillin-resistant Staphylococcus aureus
Daniel, Anu ; Euler, Chad ; Collin, Mattias LU
; Chahales, Peter
; Gorelick, Kenneth J.
and Fischetti, Vincent A.
(2010)
In Antimicrobial Agents and Chemotherapy
54(4).
p.1603-1612
- 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... (More)
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.
(Less)
- author
- Daniel, Anu
; Euler, Chad
; Collin, Mattias
LU
; Chahales, Peter
; Gorelick, Kenneth J.
and Fischetti, Vincent A.
- publishing date
- 2010-04-01
- type
- Contribution to journal
- publication status
- published
- in
- Antimicrobial Agents and Chemotherapy
- volume
- 54
- issue
- 4
- pages
- 10 pages
- publisher
- American Society for Microbiology
- external identifiers
-
- scopus:77950126213
- pmid:20086153
- ISSN
- 0066-4804
- DOI
- 10.1128/AAC.01625-09
- language
- English
- LU publication?
- no
- id
- 7cc8fa56-5adc-425a-9fc4-f4689f12773f
- date added to LUP
- 2018-10-30 19:49:57
- date last changed
- 2024-07-08 22:47:52
@article{7cc8fa56-5adc-425a-9fc4-f4689f12773f,
abstract = {{<p>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.</p>}},
author = {{Daniel, Anu and Euler, Chad and Collin, Mattias and Chahales, Peter and Gorelick, Kenneth J. and Fischetti, Vincent A.}},
issn = {{0066-4804}},
language = {{eng}},
month = {{04}},
number = {{4}},
pages = {{1603--1612}},
publisher = {{American Society for Microbiology}},
series = {{Antimicrobial Agents and Chemotherapy}},
title = {{Synergism between a novel chimeric lysin and oxacillin protects against infection by methicillin-resistant Staphylococcus aureus}},
url = {{http://dx.doi.org/10.1128/AAC.01625-09}},
doi = {{10.1128/AAC.01625-09}},
volume = {{54}},
year = {{2010}},
}