nxl-103 and quinupristin-dalfopristin

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.

Topics: Anti-Bacterial Agents; Crystallography, X-Ray; Drug Combinations; Drug Synergism; Enterococcus faecalis; Escherichia coli; Haemophilus influenzae; Microbial Sensitivity Tests; Protein Biosynthesis; Ribosomes; Staphylococcus aureus; Streptococcus pneumoniae; Streptogramin A; Streptogramin B; Streptogramins; Virginiamycin

A new streptogramin antibiotic XRP 2868 was compared with quinupristin-dalfopristin for inhibitory activities against antibiotic-resistant Haemophilus influenzae, Staphylococcus aureus, and Streptococcus pneumoniae. In each organism examined, XRP 2868 had an IC(50) that was twofold to fivefold lower than quinupristin-dalfopristin, for inhibition of cell viability, protein synthesis, and ribosomal subunit formation.

Topics: Anti-Bacterial Agents; Bacterial Proteins; Drug Combinations; Drug Resistance, Bacterial; Haemophilus influenzae; Ribosomes; Staphylococcus aureus; Streptococcus pneumoniae; Streptogramin A; Streptogramin B; Virginiamycin