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dc.contributor.authorWalsh, Fionaen
dc.date.accessioned2018-01-31T11:39:41Z
dc.date.available2018-01-31T11:39:41Z
dc.date.issued2003en
dc.identifier.urihttp://hdl.handle.net/1842/27611
dc.description.abstracten
dc.description.abstractRespiratory tract infections are a serious cause ofmorbidity and mortality throughout the world. The most frequent causes of infection are Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis and atypical pathogens such as Chlamydophila pneumoniae. These infections are treated traditionally with antimicrobial agents, mainly the penicillins and macrolides. However, the incidence ofmacrolide resistance has increased markedly over the past 10 years, particularly in France, Belgium and Italy. Therefore, new compounds like telithromycin, an erythromycin derivative called a ketolide (K), have been developed to overcome this problem.en
dc.description.abstractIn this study, clinical isolates ofS. pneumoniae, H. influenzae and M. catarrhalis were tested in vitro against a range ofantimicrobial agents, including telithromycin, to investigate the efficacy ofthis new drug. Telithromycin showed excellent activity against S. pneumoniae, including macrolide resistant strains, but its activity was not as high against M. catarrhalis or H. influenzae. For M. catarrhalis the minimum inhibitory concentration (MIC) oftelithromycin was similar to that of the macrolides. With regard to H. influenzae telithromycin had higher activity than erythromycin and clarithromycin.en
dc.description.abstractThe ermB and mefA/E genes mediate resistance to macrolides in S. pneumoniae in most cases. The ermB gene confers resistance to macrolide, lincosamide and streptogramin B (MLSB) antimicrobial agents by methylation ofpart oftheir ii ribosomal binding site. The mefA/E gene mediates efflux of 14- and 15-membered macrolides. Recent investigations have also implicated mutations in the 23S rRNA site ofMLSbK interactions with macrolide and, in certain cases, ketolide resistance. Alterations oftwo ribosomal proteins L4 and L22 have also been associated with increased MLSBK MICs and resistance.en
dc.description.abstractIn this study in vitro mutants were generated from three S. pneumoniae strains, 02J1095 (ermB positive), 02J1175 {mefA/E positive) and NCTC 13593 (MLSBK sensitive), on telithromycin. The MICs ofthe final generation mutants of each parent were increased in comparison to the parent but only the mutants from the macrolide resistant parents, 02J1095 and 02J1175, were telithromycin resistant. In order to ascertain the mechanism used by these telithromycin resistant mutants to achieve resistance, the ermB gene and upstream region, the mefA/E gene, the 23 S rRNA genes encoding domains II and V and the L4 and L22 riboprotein genes were amplified by PCR and sequenced. No alterations were located in any ofthe genes of the 02J1175 mutants investigated. No changes were present in the ermB genes or upstream regions, the 23 S rRNA genes or the L4 or L22 riboprotein genes ofthe 02J1095 mutants except J III 8. J III 8 had a telithromycin MIC of>32mg/L and was a second-generation mutant of 02J1095. In this strain two mutations were present. The first was a 94K to Q94 amino acid mutation in the L22 riboprotein. The second was a 208 base pair deletion in the upstream region ofthe ermB gene containing the control peptide and one oftwo ribosome-binding sites. This region controls the expression ofthe ermB gene and hence methylase production. These mutations either alone or together were not present in any other mutant. They have not been described previously in S. pneumoniae. These mutations, while novel, do not alone explain the development oftelithromycin resistance in S. pneumoniae. They do however; give an insight into how telithromycin interacts with the ribosome and the potential mechanisms clinical isolates may develop when telithromycin is introduced into the community.en
dc.publisherThe University of Edinburghen
dc.relation.ispartofAnnexe Thesis Digitisation Project 2017 Block 16en
dc.relation.isreferencedbyAlready catalogueden
dc.titleTelithromycin: the first ketolide, the interactions and alterationsen
dc.typeThesis or Dissertationen
dc.type.qualificationlevelDoctoralen
dc.type.qualificationnamePhD Doctor of Philosophyen


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