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Antimicrobial Agents and Chemotherapy, June 2006, p. 2137-2145, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.00039-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Genetic Changes That Correlate with Reduced Susceptibility to Daptomycin in Staphylococcus aureus

Lisa Friedman,* Jeff D. Alder, and Jared A. Silverman

Cubist Pharmaceuticals, Inc., 65 Hayden Ave., Lexington, Massachusetts 02421

Received 10 January 2006/ Returned for modification 26 February 2006/ Accepted 13 March 2006

Daptomycin is a lipopeptide antibiotic with potent activity against gram-positive bacteria. Complete-genome comparisons of laboratory-derived Staphylococcus aureus with decreased susceptibility to daptomycin and their susceptible parent were used to identify genes that contribute to reduced susceptibility to daptomycin. Selective pressure of growth in sublethal concentrations of daptomycin resulted in the accumulation of mutations over time correlating with incremental decreases in susceptibility. Single point mutations resulting in amino acid substitutions occurred in three distinct proteins: MprF, a lysylphosphatidylglycerol synthetase; YycG, a histidine kinase; and RpoB and RpoC, the ß and ß' subunits of RNA polymerase. Sequence analysis of mprF, yycF, yycG, rpoB, and rpoC in clinical isolates that showed treatment-emergent increases in daptomycin MICs revealed point mutations in mprF and a nucleotide insertion in yycG, suggesting a role for these genes in decreased susceptibility to daptomycin in the hospital setting.

* Corresponding author. Mailing address: Cubist Pharmaceuticals, Inc., 65 Hayden Ave., Lexington, MA 02421. Phone: (781) 860-8543. Fax: (781) 861-1164. E-mail: lisa.friedman{at}cubist.com.

Antimicrobial Agents and Chemotherapy, June 2006, p. 2137-2145, Vol. 50, No. 6
0066-4804/06/$08.00+0     doi:10.1128/AAC.00039-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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