aureus or Streptococcus pyogenes and is currently the only clinically used streptogramin antibiotic. #HALF LIFE SOURCE SYNERGY SKIN#Synercid was approved in 1999 for the treatment of life-threatening infections caused by vancomycin-resistant Enterococcus faecium (VREF) and complicated skin and skin structure infections (cSSSIs) caused by S. To counteract the spread of methicillin-resistant Staphylococcus aureus (MRSA) in hospitals in the 1990s, Synercid was developed as a 70:30 (wt/wt) mixture of dalfopristin to quinupristin. Arrows indicate conformational changes of rRNA nucleotides upon binding of the different streptogramin compounds. Hydrogen bonds in the vacant ribosome in panel F are shown by green dashed lines. (C to G) Hydrogen bonds are indicated by red dashed lines. (G) Interaction of linopristin (cyan) and quinupristin (salmon) with K90 of ribosomal protein L22. Identical changes are observed in the structure of dalfopristin under hydrolyzing conditions. (F) Conformational changes between the vacant ribosome (green) and the NXL 103 bound ribosome (cyan) are shown. The asterisk indicates the position of U2585 when bound to either dalfopristin under hydrolytic conditions or NXL 103. Adjacent nucleotides, the flopristin, and the dalfopristin component are shown by thin bonds. (E) U2585 assumes different positions in the vacant 70S ribosome (green) and the 70S ribosome in complex with either NXL 103 (cyan) or Synercid (salmon) and is shown by thick bonds. Residue A2062 in the vacant 70S ribosome is shown in transparent green. (C and D) Unbiased F obs − F calc difference density shown as mesh with chemical structure of Synercid and NXL 103, respectively. (B) Chemical structure of streptogramin antibiotics, with differences indicated in red. Streptogramin A (yellow) and streptogramin B (green) are shown. (A) Cross-section through the bacterial 50S subunit with the peptidyl transferase center (PTC) and the exit tunnel labeled. Structures of streptogramins bound to the E. Streptogramin antibiotics have been used as growth promoters in food-producing animals for >50 years ( 4) but only began to be used to treat human infections with the approval of dalfopristin-quinupristin (Synercid), an injectable pair of streptogramin antibiotics ( 5), in 1999. Streptogramin antibiotics are depsipeptides consisting of two chemically distinct types, a smaller type A and a larger type B. The streptogramin antibiotics produced by some Streptomyces strains inhibit protein synthesis by interfering with peptide bond formation and by blocking the peptide exit tunnel in the large (50S) ribosomal subunit, which prevents the extension of the polypeptide chain ( Fig. Antibiotics that target the bacterial ribosome specifically interfere with key processes of protein synthesis, such as mRNA decoding and peptide bond formation ( 3). Despite the constant need for new antibiotics, the number of new antibiotics approved by the FDA has significantly decreased over the last decade ( 1, 2). Based on conservative assumptions made by the Centers for Disease Control and Prevention (CDC), at least two million people acquire life-threatening infections caused by antibiotic-resistant bacterial strains in the United States every year, resulting in 23,000 deaths. 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.īacterial infections caused by antibiotic-resistant clinical isolates are an emerging medical threat. Replacement of the diethylaminoethylsulfonyl group in dalfopristin by a nonhydrolyzable group may therefore be beneficial for 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. However, in transcription-coupled translation assays, only combinations that include dalfopristin, the streptogramin A component of Synercid, show synergy. The streptogramin A and B components in Synercid and NXL 103 exhibit synergistic antimicrobial activity against certain pathogenic bacteria. We further analyzed the activity of the streptogramin components individually and in combination. 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. Streptogramin antibiotics are divided into types A and B, which in combination can act synergistically.
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