Two New Mechanisms of Macrolide Resistance in Clinical Strains of
            <i>Streptococcus pneumoniae</i>
            from Eastern Europe and North America

Tait-Kamradt, Amelia; Davies, Todd A.; Appelbaum, Peter C.; Depardieu, Florence; Courvalin, Patrice; Petitpas, Joan W.; Wondrack, L; Walker, Andre; Jacobs, Michael; Sutcliffe, Joyce A.

doi:10.1128/aac.44.12.3395-3401.2000

Cited by 241 publications

(214 citation statements)

References 52 publications

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“…The ML phenotype can be caused by another mutation, A2059G, conferring resistance to 14-, 15-, 16-membered macrolides and lincosamides [44]. Likewise, mutations occurring in ribosomal protein L4 or L22 confer macrolide resistance [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

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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.

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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

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“…Macrolide resistance in Streptococcus pneumoniae is due to either target site modification-generally depending on a posttranscriptional modification of 23S rRNA mediated by ermclass methylases (39) or less often on mutations in 23S rRNA or ribosomal proteins (7,37,38)-or active efflux. In this study, 120 erythromycin-resistant pneumococci were investigated for macrolide resistance phenotypes and genotypes, with emphasis on the discrimination between mef(A) and mef(E).…”

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confidence: 99%

Phenotypes and Genotypes of Erythromycin-Resistant Pneumococci in Italy

et al. 2003

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Of 120 erythromycin-resistant pneumococci isolated in Italian hospitals, 39 (32.5%) were M-type isolates, carrying the mef gene alone. The mef gene was also detected, together with erm(AM), in one constitutively resistant isolate and in five isolates of the partially inducible phenotype. Among the 45 mef-positive isolates, 25 (55.6%) carried mef(A) and 20 (44.4%) carried mef(E) as observed from PCR-restriction fragment length polymorphism analysis of a 1,743-bp amplicon. The same result was obtained by a similar method applied to a more common 348-bp amplicon.Macrolide resistance in Streptococcus pneumoniae is due to either target site modification-generally depending on a posttranscriptional modification of 23S rRNA mediated by ermclass methylases (39) or less often on mutations in 23S rRNA or ribosomal proteins (7, 37, 38)-or active efflux. In this study, 120 erythromycin-resistant pneumococci were investigated for macrolide resistance phenotypes and genotypes, with emphasis on the discrimination between mef(A) and mef(E).Efflux-mediated resistance. The efflux mechanism, which reduces the intracellular antibiotic concentration to subtoxic levels (40), is associated with a resistance pattern (M phenotype) characterized by resistance, among macrolides-lincosamidesstreptogramin B (MLS), only to 14-and 15-membered macrolides, usually at a low level (34). M-type resistance is mediated by the mef gene, two variants of which are conventionally described: one, mef(A), originally discovered in Streptococcus pyogenes (5), and the other, mef(E), originally discovered in S. pneumoniae (36). Considering that the mef genes are detected mostly by a PCR method unable to distinguish between the two variants (33) and that mef(A) and mef(E) have 90% identity (36), they are regarded as a single gene class, designated mef(A) (28). However, mef(A) and mef(E) have recently been shown to be carried by different genetic elements in S. pneumoniae, which are inserted at different sites in the chromosome. Both elements carry, adjacent to mef, an open reading frame showing homology to the msr(A) gene associated with macrolide efflux in Staphylococcus aureus (6,12,29). Due to a number of important differences in the properties of mef(A)-and mef(E)-carrying pneumococci, it has been recommended that the distinction between the two genes be maintained (6).Bacterial strains and typing. The 120 erythromycin-resistant pneumococci studied (for which the MIC of erythromycin was Ն1 g/ml) were independent isolates, collected from several laboratories throughout Italy between 1999 and 2002. All were clinical strains, isolated from a variety of clinical specimens (upper respiratory tract material, sputum, blood, cerebrospinal fluid). Multiple isolates from the same patient were excluded.Strain identification was confirmed in our laboratory by conventional tests such as susceptibility to optochin and solubility in bile and by employing the API system (BioMérieux, Marcyl'Etoile, France). Serotyping, done by the capsular swelling test using specific anti...

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“…Recently, mutations in the 23S rRNA or ribosomal proteins of S. pneumoniae have been found to confer erythromycin (ERY) resistance in some clinical isolates (30).…”

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confidence: 99%

Macrolide Efflux Genes mef (A) and mef (E) Are Carried by Different Genetic Elements in Streptococcus pneumoniae

et al. 2002

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Susceptibilities to macrolides were evaluated in 267 Streptococcus pneumoniae isolates, of which 182 were from patients with invasive diseases and 85 were from healthy carriers. Of the 98 resistant isolates, 20 strains showed an M phenotype and carried mef. Strains that carried both mef(A) and mef(E) were found: 17 strains carried mef(A) and 3 carried mef(E). The characteristics of the strains carrying the mef genes and the properties of the mef-containing elements were studied. Strains carrying mef(A) belonged to serotype 14, were susceptible to all the antibiotics tested except erythromycin, and appeared to be clonally related by pulsed-field gel electrophoresis (PFGE). The three mef(E) strains belonged to different serotypes, showed different susceptibility profiles, and did not appear to be related by PFGE. The sequences of a fragment of the mef-containing element, which encompassed mef and the msr(A) homolog, were identical among the three mef(E)-positive strains and among the three mef(A)-positive strains, although there were differences between the sequences for the two variants at 168 positions. In all mef(A)-positive strains, the mef element was inserted in celB, which led to impairment of the competence of the strains. In line with insertion of the mef(E) element at a different site, the competence of the mef(E)-positive strains was maintained. Transfer of erythromycin resistance by conjugation was obtained from two of three mef(A) strains but from none of three mef(E) strains. Due to the important different characteristics of the strains carrying mef(A) or mef(E), we suggest that the distinction between the two genes be maintained.Macrolide resistance in Streptococcus pneumoniae is typically due to acquisition of the erm(B) gene, which mediates ribosomal modification (10), or the mef gene, which encodes a drug efflux pump (28). Recently, mutations in the 23S rRNA or ribosomal proteins of S. pneumoniae have been found to confer erythromycin (ERY) resistance in some clinical isolates (30).The Mef pump confers a low to moderate level of resistance to 14-and 15-membered macrolides but not to lincosamide or streptogramin B antibiotics (M phenotype). Of the two variants of the mef gene, mef(A) was originally found in Streptococcus pyogenes (3) and mef(E) was originally found in S. pneumoniae (29). mef(A) and mef(E) are 90% identical at the nucleotide level and were assigned to the same class of macrolide resistance determinants (22). In most subsequent studies, mef was detected by a PCR assay that did not distinguish between the two variants (27). However, the two variants were considered species specific; therefore, if a mef gene was found in S. pneumoniae, it was generally assumed to be mef(E) (9, 16, 26). However, mef(A) was shown to be present in macrolideresistant Italian isolates of S. pneumoniae (18).Genetic elements carrying mef genes in S. pneumoniae were recently detected and characterized. The mef(A)-carrying element is a 7.2-kb defective transposon (Tn1207.1) that contains eight open reading fra...

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Two New Mechanisms of Macrolide Resistance in Clinical Strains of Streptococcus pneumoniae from Eastern Europe and North America

Cited by 241 publications

References 52 publications

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

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

Phenotypes and Genotypes of Erythromycin-Resistant Pneumococci in Italy

Macrolide Efflux Genes mef (A) and mef (E) Are Carried by Different Genetic Elements in Streptococcus pneumoniae

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