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PMID: 16723576 Published · ppublish English Comparative Study Journal Article

Genetic changes that correlate with reduced susceptibility to daptomycin in Staphylococcus aureus.

Antimicrobial agents and chemotherapy ·Vol. 50 ·No. 6 ·2006-06-00 ·Pages 2137-45

Friedman L, Alder JD, Silverman JA

Abstract

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 beta and beta' 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.

MeSH Terms
Amino Acid Substitution Anti-Bacterial Agents/pharmacology Bacterial Proteins/physiology Daptomycin/pharmacology Drug Resistance Genes, Bacterial Humans Microbial Sensitivity Tests Selection, Genetic Sequence Analysis, DNA Staphylococcus aureus/drug effects,genetics,growth & development,isolation & purification
Chemicals
Anti-Bacterial Agents Bacterial Proteins Daptomycin
Authors & Affiliations
3 authors, click to expand affiliations / ORCID
Friedman Lisa
Cubist Pharmaceuticals, Inc., Lexington, MA 02421, USA. lisa.friedman@cubist.com
Alder Jeff D
Silverman Jared A
References (43)
43 references, click to expand
  1. Mutation discovery in bacterial genomes: metronidazole resistance in Helicobacter pylori.
    Nat Methods. 2005 Dec;2(12):951-3 PMID: 16299480
  2. Daptomycin in vitro activity tested against Gram-positive strains collected from European and Latin American medical centers in 2003.
    J Chemother. 2005 Oct;17(5):477-83 PMID: 16323435
  3. Role in cell permeability of an essential two-component system in Staphylococcus aureus.
    J Bacteriol. 1999 Jun;181(12):3666-73 PMID: 10368139
  4. Genes controlled by the essential YycG/YycF two-component system of Bacillus subtilis revealed through a novel hybrid regulator approach.
    Mol Microbiol. 2003 Sep;49(6):1639-55 PMID: 12950927
  5. Streptolydigin resistance can be conferred by alterations to either the beta or beta' subunits of Bacillus subtilis RNA polymerase.
    J Biol Chem. 1995 Oct 13;270(41):23930-3 PMID: 7592585
  6. Mutations of bacterial RNA polymerase leading to resistance to microcin j25.
    J Biol Chem. 2002 Dec 27;277(52):50867-75 PMID: 12401787
  7. Complete genomes of two clinical Staphylococcus aureus strains: evidence for the rapid evolution of virulence and drug resistance.
    Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9786-91 PMID: 15213324
  8. Analysis of gyrA and grlA mutations in stepwise-selected ciprofloxacin-resistant mutants of Staphylococcus aureus.
    Antimicrob Agents Chemother. 1995 Jul;39(7):1554-8 PMID: 7492103
  9. Insights on antibiotic resistance of Staphylococcus aureus from its whole genome: genomic island SCC.
    Drug Resist Updat. 2003 Feb;6(1):41-52 PMID: 12654286
  10. Biochemical characterization of the first essential two-component signal transduction system from Staphylococcus aureus and Streptococcus pneumoniae.
    J Mol Microbiol Biotechnol. 2003;5(4):252-60 PMID: 12867749
  11. Inactivation of mprF affects vancomycin susceptibility in Staphylococcus aureus.
    Biochim Biophys Acta. 2003 May 2;1621(2):117-21 PMID: 12726988
  12. Tracking the evolution of the SARS coronavirus using high-throughput, high-density resequencing arrays.
    Genome Res. 2004 Mar;14(3):398-405 PMID: 14993206
  13. MprF-mediated biosynthesis of lysylphosphatidylglycerol, an important determinant in staphylococcal defensin resistance.
    FEMS Microbiol Lett. 2004 Feb 9;231(1):67-71 PMID: 14769468
  14. Cloning and primary structure of Staphylococcus aureus DNA topoisomerase IV: a primary target of fluoroquinolones.
    Mol Microbiol. 1994 Aug;13(4):641-53 PMID: 7997176
  15. Development of Daptomycin resistance in vivo in methicillin-resistant Staphylococcus aureus.
    J Clin Microbiol. 2005 Oct;43(10):5285-7 PMID: 16207998
  16. Reduced content of lysyl-phosphatidylglycerol in the cytoplasmic membrane affects susceptibility to moenomycin, as well as vancomycin, gentamicin, and antimicrobial peptides, in Staphylococcus aureus.
    Antimicrob Agents Chemother. 2004 Dec;48(12):4800-7 PMID: 15561859
  17. The essential two-component regulatory system encoded by yycF and yycG modulates expression of the ftsAZ operon in Bacillus subtilis.
    Microbiology. 2000 Jul;146 ( Pt 7):1573-83 PMID: 10878122
  18. Characterization of the Staphylococcus aureus mprF gene, involved in lysinylation of phosphatidylglycerol.
    Microbiology. 2004 Jan;150(Pt 1):45-51 PMID: 14702396
  19. MprF-mediated lysinylation of phospholipids in Staphylococcus aureus leads to protection against oxygen-independent neutrophil killing.
    Infect Immun. 2003 Jan;71(1):546-9 PMID: 12496209
  20. Streptolydigin-resistant mutants in an evolutionarily conserved region of the beta' subunit of Escherichia coli RNA polymerase.
    J Biol Chem. 1995 Oct 13;270(41):23926-9 PMID: 7592584
  21. Inhibitory effects of basic or neutral phospholipid on acidic phospholipid-mediated dissociation of adenine nucleotide bound to DnaA protein, the initiator of chromosomal DNA replication.
    J Biol Chem. 2003 Aug 1;278(31):28778-86 PMID: 12767975
  22. Genome and virulence determinants of high virulence community-acquired MRSA.
    Lancet. 2002 May 25;359(9320):1819-27 PMID: 12044378
  23. Linezolid resistance in Staphylococcus aureus: characterization and stability of resistant phenotype.
    J Infect Dis. 2002 Dec 1;186(11):1603-7 PMID: 12447736
  24. Resistance to quinupristin-dalfopristin due to mutation of L22 ribosomal protein in Staphylococcus aureus.
    Antimicrob Agents Chemother. 2002 Jul;46(7):2200-7 PMID: 12069975
  25. Fluoroquinolone resistance among Gram-positive cocci.
    Lancet Infect Dis. 2002 Sep;2(9):530-8 PMID: 12206969
  26. Whole genome sequencing of meticillin-resistant Staphylococcus aureus.
    Lancet. 2001 Apr 21;357(9264):1225-40 PMID: 11418146
  27. Evolutionary genomics of Staphylococcus aureus: insights into the origin of methicillin-resistant strains and the toxic shock syndrome epidemic.
    Proc Natl Acad Sci U S A. 2001 Jul 17;98(15):8821-6 PMID: 11447287
  28. Escherichia coli RNA polymerase is the target of the cyclopeptide antibiotic microcin J25.
    J Bacteriol. 2001 Aug;183(15):4543-50 PMID: 11443089
  29. Resistance studies with daptomycin.
    Antimicrob Agents Chemother. 2001 Jun;45(6):1799-802 PMID: 11353628
  30. Clinical progression of methicillin-resistant Staphylococcus aureus vertebral osteomyelitis associated with reduced susceptibility to daptomycin.
    J Clin Microbiol. 2005 Oct;43(10):5384-7 PMID: 16208025
  31. Identification of genes controlled by the essential YycG/YycF two-component system of Staphylococcus aureus.
    J Bacteriol. 2004 Feb;186(4):1175-81 PMID: 14762013
  32. Structural transitions as determinants of the action of the calcium-dependent antibiotic daptomycin.
    Chem Biol. 2004 Jul;11(7):949-57 PMID: 15271353
  33. Insights on evolution of virulence and resistance from the complete genome analysis of an early methicillin-resistant Staphylococcus aureus strain and a biofilm-producing methicillin-resistant Staphylococcus epidermidis strain.
    J Bacteriol. 2005 Apr;187(7):2426-38 PMID: 15774886
  34. Activity of daptomycin against susceptible and multidrug-resistant Gram-positive pathogens collected in the SECURE study (Europe) during 2000-2001.
    J Antimicrob Chemother. 2003 Mar;51(3):639-49 PMID: 12615866
  35. Biological cost of rifampin resistance from the perspective of Staphylococcus aureus.
    Antimicrob Agents Chemother. 2002 Nov;46(11):3381-5 PMID: 12384339
  36. Daptomycin: a new drug class for the treatment of Gram-positive infections.
    Drugs Today (Barc). 2005 Feb;41(2):81-90 PMID: 15821781
  37. Cloning and sequencing of the gene, fmtC, which affects oxacillin resistance in methicillin-resistant Staphylococcus aureus.
    FEMS Microbiol Lett. 2001 Sep 11;203(1):49-54 PMID: 11557139
  38. Correlation of daptomycin bactericidal activity and membrane depolarization in Staphylococcus aureus.
    Antimicrob Agents Chemother. 2003 Aug;47(8):2538-44 PMID: 12878516
  39. Mechanism of action of the oxazolidinone antibacterial agents.
    Expert Opin Investig Drugs. 1999 Aug;8(8):1195-202 PMID: 15992144
  40. Staphylococcus aureus resistance to human defensins and evasion of neutrophil killing via the novel virulence factor MprF is based on modification of membrane lipids with l-lysine.
    J Exp Med. 2001 May 7;193(9):1067-76 PMID: 11342591
  41. Staphylococcus aureus susceptibility to innate antimicrobial peptides, beta-defensins and CAP18, expressed by human keratinocytes.
    Infect Immun. 2003 Jul;71(7):3730-9 PMID: 12819054
  42. Nucleotide substitution and recombination at orthologous loci in Staphylococcus aureus.
    J Bacteriol. 2005 Apr;187(8):2698-704 PMID: 15805516
  43. Genetic analysis of zwittermicin A resistance in Escherichia coli: effects on membrane potential and RNA polymerase.
    Mol Microbiol. 1998 Jan;27(2):311-22 PMID: 9484887
Article Info
Journal
Antimicrobial agents and chemotherapy
Abbr.
Antimicrob Agents Chemother
ISSN
0066-4804
DOI
10.1128/AAC.00039-06
Email
lisa.friedman@cubist.com
Published
2006-06-00
Pages
2137-45
Language
English
Region
United States
NLM ID
0315061
PMCID
PMC1479123
Subset
IM
External Links
PubMed source DOI: 10.1128/AAC.00039-06 PMC Full Text View journal details
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