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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 beta -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 beta -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 beta -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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