1 The JONES Group/JMI Laboratories, 345 Beaver Kreek Centre, Suite A, North Liberty, IA 52317; 2 Tufts University School of Medicine, Boston, MA, USA
Received 15 December 2003; returned 20 January 2004; revised 8 February 2004; accepted 13 February 2004
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Abstract |
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Materials and methods: A total of 45 strains from three genera (six species groups) were tested by reference broth microdilution methods. The mechanism of resistance to the oxazolidinone was determined by sequencing of the gene encoding the ribosomal target.
Results: NVP PDF-713 retained activity against linezolid-resistant staphylococci (MIC range 0.252 mg/L), Streptococcus oralis (MIC 0.5 mg/L), Enterococcus faecalis (MIC range 24 mg/L) and Enterococcus faecium (MIC range 0.54 mg/L). Quinupristin/dalfopristin-resistant E. faecium (MIC range 12 mg/L) and staphylococci (MIC range 0.122 mg/L) were also inhibited by NVP PDF-713. Many (10 of 13 strains) of the linezolid-resistant enterococci were resistant to vancomycin and these clinical strains had a G2576U ribosomal target mutation.
Conclusions: NVP PDF-713 appears to be a promising clinical candidate among the peptide deformylase inhibitors for the treatment of infections caused by Gram-positive organisms that possess resistances to oxazolidinones or streptogramin combinations.
Keywords: streptococci, enterococci, staphylococci, streptogramins, oxazolidinones
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Introduction |
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In this investigation, NVP PDF-713, a new peptide deformylase inhibitor from a novel series of compounds,13 was testedusing reference susceptibility test methods14,15against a collection of recent clinical isolates having documented resistances to linezolid or quinupristin/dalfopristin.
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Materials and methods |
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A total of 45 organisms, originally isolated at resistance surveillance sites in the USA, Canada, Brazil and Europe, were selected from the stock culture collection (20012002) of JMI Laboratories (North Liberty, IA, USA). These organisms included Enterococcus faecalis (linezolid-resistant, three strains; quinupristin/dalfopristin resistance was intrinsic), Enterococcus faecium (linezolid-resistant, 10 strains; quinupristin/dalfopristin-resistant, six strains), S. aureus (linezolid-resistant, five strains; quinupristin/dalfopristin-resistant, 10 strains), coagulase-negative staphylococci (linezolid-resistant, one strain; quinupristin/dalfopristin-resistant, nine strains) and Streptococcus oralis (linezolid-resistant, one strain). Definitions of resistance were those published by the NCCLS.14,15
Susceptibility testing
All susceptibility tests were performed using NCCLS M7-A6 methods14 with 2%5% lysed horse blood supplement for the fastidious streptococci. Cation-adjusted MuellerHinton broth was used for all other tested species. The mechanisms of resistance for all linezolid-resistant strains (MICs 8 mg/L) were confirmed by gene sequencing of the ribosomal target3 and the detection of a G2576U mutation. The MICs of quinupristin/dalfopristin for quinupristin/dalfopristin-resistant strains were phenotypically confirmed by disc diffusion and Etest (AB Biodisk, Solna, Sweden) to have an MIC at
4 mg/L. PCR tests for vatD and vatE were negative.1
Quality control (QC) of the NVP PDF-713 MIC results was performed using acceptable MIC ranges reported by Anderegg et al.16 for QC strains S. aureus ATCC 29213, Streptococcus pneumoniae ATCC 49619 and E. faecalis ATCC 29212. All QC results for NVP PDF-71316 and comparison agents used to categorize resistant isolates (linezolid, quinupristin/dalfopristin, vancomycin) were within NCCLS15 published limits. Trays were manufactured by TREK Diagnostics (Cleveland, OH, USA) to specified NCCLS standards.14 The proposed or tentative susceptible breakpoint for NVP PDF-713 to be applied by clinical trial laboratories was 8 mg/L based on pharmacokinetic/pharmacodynamic characteristics of this compound and similar peptide deformylase inhibitors.17
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Results and discussion |
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Acknowledgements |
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Footnotes |
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References |
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2 . Livermore, D. M. (2003). Bacterial resistance: origins, epidemiology, and impact. Clinical Infectious Diseases 36, Suppl. 1, S11S23.[CrossRef][ISI][Medline]
3
.
Mutnick, A. H., Enne, V. & Jones, R. N. (2003). Linezolid resistance since 2001: SENTRY Antimicrobial Surveillance Program. Annals of Pharmacotherapy 37, 76974.
4 . Giglione, C., Pierre, M. & Meinnel, T. (2000). Peptide deformylase as a target for new generation, broad-spectrum antimicrobial agents. Molecular Microbiology 36, 1197205.[CrossRef][ISI][Medline]
5 . Yuan, Z., Trias, J.& White, R. J. (2001). Deformylase as a novel antibacterial target. Drug Discovery Today 6, 95461.[CrossRef][ISI][Medline]
6 . Waller, A. S. & Clements, J. M. (2002). Novel approaches to antimicrobial therapy: peptide deformylase. Current Opinion in Drug Discovery and Development 5, 78592.
7 . Bowker, K. E., Noel, A. R. & MacGowan, A. P. (2003). In vitro activities of nine peptide deformylase inhibitors and five comparator agents against respiratory and skin pathogens. International Journal of Antimicrobial Agents 22, 55761.[CrossRef][ISI][Medline]
8
.
Jain, R., Sundram, A., Lopez, S. et al. (2003). -Substituted hydroxamic acids as novel bacterial deformylase inhibitor-based antibacterial agents. Bioorganic and Medicinal Chemistry Letters 13, 42238.[CrossRef][Medline]
9
.
Apfel, C. M., Locher, H., Evers, S. et al. (2001). Peptide deformylase as an antibacterial drug target: target validation and resistance development. Antimicrobial Agents and Chemotherapy 45, 105864.
10 . Giglione, C. & Meinnel, T. (2001). Resistance to anti-peptide deformylase drugs. Expert Opinion on Therapeutic Targets 5, 4158.[Medline]
11
.
Margolis, P., Hackbarth, C., Lopez, S. et al. (2001). Resistance of Streptococcus pneumoniae to deformylase inhibitors is due to mutations in defB. Antimicrobial Agents and Chemotherapy 45, 24325.
12
.
Margolis, P. S., Hackbarth, C. J., Young, D. C. et al. (2000). Peptide deformylase in Staphylococcus aureus: resistance to inhibition is mediated by mutations in the formyl transferase gene. Antimicrobial Agents and Chemotherapy 44, 182531.
13
.
Chen, D., Hackbarth, C., Ni, Z. J. et al. (2004). Peptide deformylase inhibitors as antibacterial agents: Identification of VRC3375, a proline-3-alkylsuccinyl hydroxamate derivative, by using an integrated combinatorial and medicinal chemistry approach. Antimicrobial Agents and Chemotherapy 48, 25061.
14 . National Committee for Clinical Laboratory Standards. (2003). Methods for Dilution Antimicrobial Susceptibility Tests for Bacteria that Grow Aerobically. Approved Standard M7-A6. NCCLS, Wayne, PA, USA.
15 . National Committee for Clinical Laboratory Standards. (2003). Performance Standards for Antimicrobial Susceptibility Testing M100-S13. NCCLS, Wayne, PA, USA.
16 . Anderegg, T. R., Biedenbach D. J., Jones R. N. et al. (2003). Quality control guidelines for MIC susceptibility testing of NVP PDF-713, a novel peptide deformylase inhibitors. International Journal of Antimicrobial Agents 22, 846.[CrossRef][ISI][Medline]
17 . Craig, W. A. & Andes, D. (2001). In vivo pharmacodynamics of BB-83698, a deformylase inhibitor. In Programs and Abstracts of the Forty-first Interscience Conference on Antimicrobial Agents and Chemotherapy, Chicago, IL, 2001. Abstract F-355, p. 206. American Society for Microbiology, Washington, DC, USA.