Antimicrobial Activity of SCH 27899, Oligosaccharide Member of the Everninomycin Class with a Wide Gram-Positive Spectrum

Jones, Ronald N.; Barrett, Mary S.

doi:10.1111/j.1469-0691.1995.tb00022.x

Cited by 39 publications

(23 citation statements)

References 10 publications

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“…Killing curve data suggested that evernimicin is not uniformly bactericidal (9). We used a misincorporation assay to determine if evernimicin, like streptomycin, exerts its limited bactericidal effects through promotion of misreading.…”

Section: Discussionmentioning

confidence: 99%

“…One potential new agent is evernimicin (SCH 27899), a member of the everninomicin class of antibiotics isolated from Micromonospora carbonaceae (5)(6)(7). Evernimicin is an oligosaccharide antibiotic with activity against a broad range of gram-positive pathogenic bacteria including glycopeptide-resistant enterococci, methicillin-resistant staphylococci, and penicillin-resistant streptococci (9). However, the mode of action of evernimicin is unclear.…”

mentioning

confidence: 99%

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Evernimicin Binds Exclusively to the 50S Ribosomal Subunit and Inhibits Translation in Cell-Free Systems Derived from both Gram-Positive and Gram-Negative Bacteria

McNicholas¹,

Najarian²,

Mann³

et al. 2000

Antimicrob Agents Chemother

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Evernimicin (SCH 27899) is a new antibiotic with activity against a wide spectrum of gram-positive bacteria and activity against some gram-negative bacteria. Previous metabolic labeling studies indicated that evernimicin specifically inhibited protein synthesis in Staphylococcus aureus. Using a susceptible Escherichia coli strain, we demonstrated that evernimicin also inhibited protein synthesis in E. coli. In cell-free translation assays with extracts from either E. coli or S. aureus, evernimicin had a 50% inhibitory concentration of approximately 125 nM. In contrast, cell-free systems derived from wheat germ and rabbit reticulocytes were inhibited only by very high levels of evernimicin. Evernimicin did not promote transcript misreading. [14 C]evernimicin specifically bound to the 50S subunit from E. coli. Nonlinear regression analysis of binding data generated with 70S ribosomes from E. coli and S. aureus and 50S subunits from E. coli returned dissociation constants of 84, 86, and 160 nM, respectively. In binding experiments, performed in the presence of excess quantities of a selection of antibiotics known to bind to the 50S subunit, only the structurally similar drug avilamycin blocked binding of [ 14 C]evernimicin to ribosomes.The emergence of vancomycin resistance among Enterococcus spp. and the demonstration that this resistance can be transferred to Staphylococcus aureus (14) have highlighted the need for alternative regimens to combat serious infections caused by gram-positive organisms. One potential new agent is evernimicin (SCH 27899), a member of the everninomicin class of antibiotics isolated from Micromonospora carbonaceae (5-7). Evernimicin is an oligosaccharide antibiotic with activity against a broad range of gram-positive pathogenic bacteria including glycopeptide-resistant enterococci, methicillin-resistant staphylococci, and penicillin-resistant streptococci (9). However, the mode of action of evernimicin is unclear. Two studies, a genetic characterization of a Streptococcus pneumoniae strain that displayed reduced susceptibility to evernimicin (3) and a metabolic labeling study with S. aureus (T. A. Black, W. Zhao, K. J. Shaw, and R. S. Hare, Abstr. 38th Intersci. Conf. Antimicrob. Agents Chemother., abstr. C-106, p. 99, 1998), suggested that evernimicin exerts its antibacterial effects by inhibiting protein synthesis. These data are consistent with the finding that avilamycin, which is structurally similar to evernimicin (Fig. 1), also inhibits translation in vivo and in vitro (24). An indication that avilamycin and evernimicin may share similar mechanisms of action came from a survey of avilamycin-resistant enterococci, which revealed a direct correlation between avilamycin resistance and a reduced susceptibility to evernimicin (1). In this report we document the biochemical effect of evernimicin on protein synthesis. Our data demonstrate that evernimicin binds ribosomes from S. aureus and Escherichia coli at what appears to be a unique site. In addition, evernimicin inhibits in vitro pr...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Evernimicin Binds Exclusively to the 50S Ribosomal Subunit and Inhibits Translation in Cell-Free Systems Derived from both Gram-Positive and Gram-Negative Bacteria

McNicholas¹,

Najarian²,

Mann³

et al. 2000

Antimicrob Agents Chemother

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“…Evernimicin (SCH 27899) is a novel oligosaccharide antibiotic (8,22) with activity against a broad range of gram-positive pathogenic bacteria including glycopeptide-resistant enterococci, methicillin-resistant staphylococci, and penicillin-resistant streptococci (11). We previously demonstrated that evernimicin inhibits protein synthesis in Staphylococcus aureus and in a susceptible Escherichia coli strain (13).…”

mentioning

confidence: 99%

Effects of Mutations in Ribosomal Protein L16 on Susceptibility and Accumulation of Evernimicin

McNicholas¹,

Mann²,

Najarian³

et al. 2001

Antimicrob Agents Chemother

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Chemical mutagenesis of Staphylococcus aureus RN450 generated two strains that displayed a stable reduction (30-to 60-fold) in susceptibility to evernimicin. Cell-free translation reactions demonstrated that the resistance determinant was located in the ribosomal fraction. Compared to ribosomes isolated from a wild-type strain, ribosomes from the mutant strains displayed an 8-to 10-fold reduction in affinity for [ 14 C]evernimicin. In contrast, the mutants displayed no alteration in either binding affinity or in vitro susceptibility to erythromycin. Exponential cultures of the mutant strains accumulated significantly less [ 14 C]evernimicin than the wild-type strain, suggesting that accumulation is dependent on the high affinity that evernimicin displays for its binding site. Sequencing rplP (encodes ribosomal protein L16) in the mutant strains revealed a single base change in each strain, which resulted in a substitution of either cysteine or histidine for arginine at residue 51. Introduction of a multicopy plasmid carrying wild-type rplP into the mutant strains restored sensitivity to evernimicin, confirming that the alterations in rplP were responsible for the change in susceptibility. Overexpression of the mutant alleles in S. aureus RN450 had no effect on susceptibility to evernimicin, demonstrating that susceptibility is dominant over resistance.

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“…Several new drugs targeted against the ribosome are currently being developed, including the oxazolidinones (3,18). After first being identified as prospective antimicrobial agents in 1987 (32), oxazolidinones were abandoned for some time due to their high toxicity.…”

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confidence: 99%

Oxazolidinone Resistance Mutations in 23S rRNA of Escherichia coli Reveal the Central Region of Domain V as the Primary Site of Drug Action

Xiong

Kloss

Douthwaite³

et al. 2000

J Bacteriol

157

102

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Oxazolidinone antibiotics inhibit bacterial protein synthesis by interacting with the large ribosomal subunit. The structure and exact location of the oxazolidinone binding site remain obscure, as does the manner in which these drugs inhibit translation. To investigate the drug-ribosome interaction, we selected Escherichia coli oxazolidinone-resistant mutants, which contained a randomly mutagenized plasmid-borne rRNA operon. The same mutation, G2032 to A, was identified in the 23S rRNA genes of several independent resistant isolates. Engineering of this mutation by site-directed mutagenesis in the wild-type rRNA operon produced an oxazolidinone resistance phenotype, establishing that the G2032A substitution was the determinant of resistance. Engineered U and C substitutions at G2032, as well as a G2447-to-U mutation, also conferred resistance to oxazolidinone. All the characterized resistance mutations were clustered in the vicinity of the central loop of domain V of 23S rRNA, suggesting that this rRNA region plays a major role in the interaction of the drug with the ribosome. Although the central loop of domain V is an essential integral component of the ribosomal peptidyl transferase, oxazolidinones do not inhibit peptide bond formation, and thus these drugs presumably interfere with another activity associated with the peptidyl transferase center.During the course of evolution, a disproportionately large number of natural antibiotics have been selected to act upon the ribosome. In the majority of cases, these drugs bind to ribosomes by interacting directly with rRNA (8). Due to the presence of multiple copies of rRNA genes in most species, it is difficult for a sensitive organism to develop resistance by mutating the antibiotic binding site, which is probably one of the main reasons why the ribosome has been repeatedly selected as an antibiotic target.Conditions created by the extensive and sometimes uncontrolled use of natural and synthetic antibiotics for antimicrobial therapy have promoted the selection and rapid spread of resistant pathogens that exhibit high tolerance to many drugs, including those which are targeted against the ribosome. Although the occurrence of antibiotic resistance mutations in rRNA genes is fairly rare in comparison with other types of resistance, a number of such cases have been reported, especially in those pathogens which contain only one or two copies of rRNA operons in their chromosome (B. Vester and S. Douthwaite, submitted for publication).The rapidly growing incidence of drug resistance in pathogenic bacteria urges the development of new antibiotics. Several new drugs targeted against the ribosome are currently being developed, including the oxazolidinones (3, 18). After first being identified as prospective antimicrobial agents in 1987 (32), oxazolidinones were abandoned for some time due to their high toxicity. Later on, new derivatives with superior pharmacological properties were found (3, 16), and recently one of the oxazolidinone antibiotics, linezolid (Fig. 1A), has ...

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Antimicrobial Activity of SCH 27899, Oligosaccharide Member of the Everninomycin Class with a Wide Gram-Positive Spectrum

Cited by 39 publications

References 10 publications

Evernimicin Binds Exclusively to the 50S Ribosomal Subunit and Inhibits Translation in Cell-Free Systems Derived from both Gram-Positive and Gram-Negative Bacteria

Evernimicin Binds Exclusively to the 50S Ribosomal Subunit and Inhibits Translation in Cell-Free Systems Derived from both Gram-Positive and Gram-Negative Bacteria

Effects of Mutations in Ribosomal Protein L16 on Susceptibility and Accumulation of Evernimicin

Oxazolidinone Resistance Mutations in 23S rRNA of Escherichia coli Reveal the Central Region of Domain V as the Primary Site of Drug Action

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