Mutation in 23S rRNA Responsible for Resistance to 16-Membered Macrolides and Streptogramins in
            <i>Streptococcus pneumoniae</i>

Depardieu, Florence; Courvalin, Patrice

doi:10.1128/aac.45.1.319-323.2001

Cited by 119 publications

(85 citation statements)

References 30 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…This bond is reversible and could be aminolyzed by juxtaposed polyamines. It should be mentioned that mutation of A2062 to G in Streptococcus pneumoniae confers resistance to many 16-membered macrolides (41).…”

Section: Discussionmentioning

confidence: 99%

Polyamines Affect Diversely the Antibiotic Potency

Πετρόπουλος

Xaplanteri

Dinos

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

The effects of spermine on peptidyltransferase inhibition by an aminohexosylcytosine nucleoside, blasticidin S, and by a macrolide, spiramycin, were investigated in a model system derived from Escherichia coli, in which a peptide bond is formed between puromycin and AcPhe-tRNA bound at the P-site of poly(U)-programmed ribosomes. Kinetics revealed that blasticidin S, after a transient phase of interference with the A-site, is slowly accommodated near to the P-site so that peptide bond is still formed but with a lower catalytic rate constant. At high concentrations of blasticidin S (>10 ؋ K i ), a second drug molecule binds to a weaker binding site on ribosomes, and this may account for the onset of a subsequent mixed-noncompetitive inhibition phase. Spermine enhances the blasticidin S inhibitory effect by facilitating the drug accommodation to both sites. On the other hand, spiramycin (A) was found competing with puromycin for the A-site of AcPhe-tRNA⅐poly(U)⅐70 S ribosomal complex (C) via a two-step mechanism, according to which the fast formation of the encounter complex CA is followed by a slow isomerization to a tighter complex, termed C*A. In contrast to that observed with blasticidin S, spermine reduced spiramycin potency by decreasing the formation and stability of complex C*A. Polyamine effects on drug binding were more pronounced when a mixture of spermine and spermidine was used, instead of spermine alone. Our kinetic results correlate well with cross-linking and crystallographic data and suggest that polyamines bound at the vicinity of the antibiotic binding pockets modulate diversely the interaction of these drugs with ribosomes.Blasticidin S and spiramycin are representatives of two distinct antibiotic families, the aminohexosylcytosine nucleosides and the 16-membered lactone ring macrolides, respectively, both of which have been proposed to inhibit protein synthesis by binding to the large ribosomal subunit. Blasticidin S consists of a cytosine bonded to a pyranose ring, to which an amino acid-like substituent is attached (see Fig. 1). Therefore, it is not surprising that blasticidin S and puromycin have been considered as iso-structural, both with one another and with the 3Ј-end of aminoacyl-tRNA (1, 2). Consistently, blasticidin S has been found to inhibit the binding of CACCA (Phe) to the A-site of ribosomes (3) and to compete with designated A-site inhibitors (4). In addition, the inhibition of peptidyl-or AcPhe 1 -puromycin synthesis by this antibiotic shows a competitive phase in concert with noncompetitive or mixed-noncompetitive phases (5, 6), a fact supporting the notion that blasticidin S influences, at least transiently, the affinity of the A-site. Further support derives from chemical probing studies in Escherichia coli ribosomes (7), suggesting that blasticidin S protects A2439, one of the three nucleosides in domain V of 23 S rRNA, which show altered chemical reactivity on removal of the aminoacyl group from A-site-bound tRNAs (8). Moreover, A2439 is one of the preferable cross-linking...

show abstract

Section: Discussionmentioning

confidence: 99%

Polyamines Affect Diversely the Antibiotic Potency

Πετρόπουλος

Xaplanteri

Dinos

et al. 2004

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Mutations in ribosomal sites engaged in macrolide activity can participate in the emergence of other macrolide resistance phenotypes, such as M16S B caused by a mutation, A2062C, conferring resistance to 16-membered macrolide and streptogramins [43]. The ML phenotype can be caused by another mutation, A2059G, conferring resistance to 14-, 15-, 16-membered macrolides and lincosamides [44].…”

Section: Aminoglycoside Resistancementioning

confidence: 99%

Molecular mechanisms and epidemiology of resistance in Streptococcus pneumoniae in the Middle East region

Moujaber

Osman

Rafei

et al. 2017

Journal of Medical Microbiology

View full text Add to dashboard Cite

Purpose. Streptococcus pneumoniae is a commensal bacterium that normally colonizes the human nasopharyngeal cavity. Once disseminated, it can cause several diseases, ranging from non-invasive infections such as acute otitis media and sinusitis through to invasive infections with higher mortality, including meningitis and septicaemia. Since the identification of the first S. pneumoniae strain with decreased susceptibility to penicillin in the 1960s, antibiotic resistance among S. pneumoniae has increased disturbingly and the mechanisms of resistance have begun to unfold.Methodology. This work briefly reviewed the available data on the molecular mechanisms underlying antimicrobial resistance and its epidemiology among pneumococcal strains in Middle Eastern countries.Key findings. Both intrinsic and acquired mechanisms (mutations, acquisition of novel mobile genetic elements and sometimes gene duplication and overexpression) affect susceptibility to a large variety of antibiotics. In Middle Eastern countries, including Lebanon, Iran, Saudi Arabia and Turkey, surveillance showed a disturbing increase in the strength and prevalence of resistance to antibiotics over the years, especially in the last decade. However, no surveillance reports were found in other Middle Eastern countries, such as Syria and Iraq.Conclusion. In order to better survey, control and prevent the emergence of multidrug-and extremely drug-resistant S. pneumoniae strains, antimicrobial stewardship, national surveillance and public awareness programmes should be developed urgently in Middle Eastern countries.

show abstract

“…Resistance is rare but has emerged in staphylococci and vancomycin-resistant Enterococcus faecium (21). Resistance in pneumococci is uncommon (Յ1.1%) (15,20), but mutations in ribosomal proteins and 23S rRNA have been reported (13,15,20). Equally rare, Q-D nonsusceptibility was previously reported in 97 of 4,626 (2.1%) pneumococcal isolates obtained from the general population by Jones et al by using Etest for determination of susceptibility (19), although the mechanism of resistance in these strains was not discussed.…”

mentioning

confidence: 99%

“…Thus, alternative antimicrobials are an ongoing need in the SCD population. Quinupristin-dalfopristin (Q-D; Synercid) is a semisynthetic, intravenous streptogramin approved for use in 1999, and the components of this compound display synergistic, bactericidal activities (8,13). Resistance is rare but has emerged in staphylococci and vancomycin-resistant Enterococcus faecium (21).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Quinupristin-Dalfopristin Nonsusceptibility in Pneumococci from Sickle Cell Disease Patients

Obert

Miller

Montgomery

et al. 2007

Antimicrob Agents Chemother

View full text Add to dashboard Cite

Sickle cell disease (SCD) is a risk factor for fatal pneumococcal infection. Nonsusceptibilty to quinupristindalfopristin (Q-D) was absent from 105 non-SCD-associated pneumococcal isolates but was present in 33/148 (22%) SCD-associated isolates. One-third of the isolates harbored a known resistance mechanism. Q-D is not optimal for use for the treatment of pneumococcal infection in SCD patients.Sickle cell disease (SCD) is characterized by a 600-fold increased risk of invasive pneumococcal infection (26). Consequently, these patients receive penicillin prophylaxis and empirical antibacterial therapy, measures which in turn promote drug resistance (24). Thus, alternative antimicrobials are an ongoing need in the SCD population. Quinupristin-dalfopristin (Q-D; Synercid) is a semisynthetic, intravenous streptogramin approved for use in 1999, and the components of this compound display synergistic, bactericidal activities (8, 13). Resistance is rare but has emerged in staphylococci and vancomycin-resistant Enterococcus faecium (21). Resistance in pneumococci is uncommon (Յ1.1%) (15,20), but mutations in ribosomal proteins and 23S rRNA have been reported (13,15,20). Equally rare, Q-D nonsusceptibility was previously reported in 97 of 4,626 (2.1%) pneumococcal isolates obtained from the general population by Jones et al. by using Etest for determination of susceptibility (19), although the mechanism of resistance in these strains was not discussed. Here, we report on the Q-D nonsusceptibilities of nasopharyngeal and invasive pneumococci in over 30% of SCD patients.Testing for susceptibility to Q-D, clindamycin, and erythromycin was performed in triplicate by Etest, according to the manufacturer's instructions, with 68 SCD-associated nasopharyngeal isolates (12) and 80 SCD-associated invasive isolates (1) collected between 1994 and 2002 and, for comparison, with 105 isolates from healthy peers of the infected patients (25,27). Twenty-five (37%) nasopharyngeal SCD-associated isolates and eight (10%) invasive SCD-associated isolates were found to be Q-D nonsusceptible (Etest MIC range, 1.5 to 2 g/ml); no high-level resistance was detected. Broth dilution MICs (10) confirmed the nonsusceptibilities of all 33 isolates * Corresponding author. Mailing address:

show abstract

Mutation in 23S rRNA Responsible for Resistance to 16-Membered Macrolides and Streptogramins in Streptococcus pneumoniae

Abstract: Streptococcus pneumoniae clinical isolate BM4455 was resistant to 16-membered macrolides and to streptogramins. This unusual resistance phenotype was due to an A 2062 C (Escherichia coli numbering) mutation in domain V of the four copies of 23S rRNA.

Cited by 119 publications

References 30 publications

Polyamines Affect Diversely the Antibiotic Potency

Polyamines Affect Diversely the Antibiotic Potency

Molecular mechanisms and epidemiology of resistance in Streptococcus pneumoniae in the Middle East region

Quinupristin-Dalfopristin Nonsusceptibility in Pneumococci from Sickle Cell Disease Patients

Contact Info

Product

Resources

About