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Antimicrobial Agents and Chemotherapy, May 2001, p. 1431-1437, Vol. 45, No. 5
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.5.1431-1437.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Mechanism and Suppression of Lysostaphin Resistance
in Oxacillin-Resistant Staphylococcus aureus
Michael W.
Climo,1,2,*
Kerstin
Ehlert,3 and
Gordon L.
Archer1,4
Departments of
Medicine1 and
Microbiology/Immunology,4 Virginia
Commonwealth University Health System, and Hunter Holmes
McGuire Veteran Affairs Medical Center,2
Richmond, Virginia, and PH-Research Antiinfectives I, Bayer
AG, D42096 Wuppertal, Germany3
Received 23 October 2000/Returned for modification 21 December
2000/Accepted 13 February 2001
The potential for the development of resistance in
oxacillin-resistant Staphylococcus aureus (ORSA) to
lysostaphin, a glycylglycine endopeptidase produced by
Staphylococcus simulans biovar staphylolyticus, was examined in vitro and in an in vivo model of infection. Following in vitro exposure of ORSA to subinhibitory concentrations of
lysostaphin, lysostaphin-resistant mutants were idenitifed among all
isolates examined. Resistance to lysostaphin was associated with a loss of resistance to
-lactams and a change in the muropeptide
interpeptide cross bridge from pentaglycine to a single glycine.
Mutations in femA, the gene required for incorporation of
the second and third glycines into the cross bridge, were found
following PCR amplification and nucleotide sequence analysis.
Complementation of lysostaphin-resistant mutants with pBBB31, which
encodes femA, restored the phenotype of oxacillin
resistance and lysostaphin susceptibility. Addition of
-lactam
antibiotics to lysostaphin in vitro prevented the development of
lysostaphin-resistant mutants. In the rabbit model of experimental
endocarditis, administration of a low dose of lysostaphin for 3 days
led predictably to the appearance of lysostaphin-resistant ORSA mutants
in vegetations. Coadministration of nafcillin with lysostaphin
prevented the emergence of lysostaphin-resistant mutants and led to a
mean reduction in aortic valve vegetation counts of 7.5 log10 CFU/g compared to those for untreated controls and
eliminated the isolation of lysostaphin-resistant mutants from aortic
valve vegetations. Treatment with nafcillin and lysostaphin given alone
led to mean reductions of 1.35 and 1.65 log10 CFU/g
respectively. In ORSA, resistance to lysostaphin was associated with
mutations in femA, but resistance could be suppressed by
the coadministration of
-lactam antibiotics.
*
Corresponding author. Mailing address: McGuire Veterans
Affairs Medical Center, 1201 Broad Rock Blvd., Section 111-C, Richmond, VA 23249. Phone: (804) 675-5018. Fax: (804) 675-5437. E-mail: Michael.Climo{at}med.va.gov.
Antimicrobial Agents and Chemotherapy, May 2001, p. 1431-1437, Vol. 45, No. 5
0066-4804/01/$04.00+0 DOI: 10.1128/AAC.45.5.1431-1437.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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