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Antimicrob Agents Chemother. 2014 Sep;58(9):5269-79. doi: 10.1128/AAC.03389-14. Epub 2014 Jun 23.

Synergy of streptogramin antibiotics occurs independently of their effects on translation.

Author information

1
Department of Molecular Cell Biology, California Institute of Quantitative Biosciences, University of California, Berkeley, California, USA.
2
AstraZeneca R&D Boston, Discovery Sciences, Waltham, Massachusetts, USA.
3
AstraZeneca R&D Boston, Infection Innovative Medicines Unit, Waltham, Massachusetts, USA.
4
Department of Molecular Cell Biology, California Institute of Quantitative Biosciences, University of California, Berkeley, California, USA jcate@lbl.gov.

Abstract

Streptogramin antibiotics are divided into types A and B, which in combination can act synergistically. We compared the molecular interactions of the streptogramin combinations Synercid (type A, dalfopristin; type B, quinupristin) and NXL 103 (type A, flopristin; type B, linopristin) with the Escherichia coli 70S ribosome by X-ray crystallography. We further analyzed the activity of the streptogramin components individually and in combination. The streptogramin A and B components in Synercid and NXL 103 exhibit synergistic antimicrobial activity against certain pathogenic bacteria. However, in transcription-coupled translation assays, only combinations that include dalfopristin, the streptogramin A component of Synercid, show synergy. Notably, the diethylaminoethylsulfonyl group in dalfopristin reduces its activity but is the basis for synergy in transcription-coupled translation assays before its rapid hydrolysis from the depsipeptide core. Replacement of the diethylaminoethylsulfonyl group in dalfopristin by a nonhydrolyzable group may therefore be beneficial for synergy. The absence of general streptogramin synergy in transcription-coupled translation assays suggests that the synergistic antimicrobial activity of streptogramins can occur independently of the effects of streptogramin on translation.

PMID:
24957822
PMCID:
PMC4135883
DOI:
10.1128/AAC.03389-14
[Indexed for MEDLINE]
Free PMC Article

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