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Antimicrobial resistance remains one of the most serious threats to modern medicine. As such, the selection and administration of antibiotics must be carefully considered, especially since the discovery of novel antimicrobial agents has reduced substantially. Agents that have previously been dismissed for unfavorable secondary activity are becoming increasingly valuable as the resistance prevalence towards the first choice antibiotic increases drastically. The aminoglycosides are a family of antibiotics that belong to this category. Shortly after their introduction to the market, problems with toxicity became apparent and they were no longer considered a drug of choice for physicians. However, increasingly worrisome resistance trends have forced physicians to reevaluate the application of aminoglycosides for life-threatening infections caused by Gram-negative pathogens. Among other resistance mechanisms, the 16S ribosomal RNA methyltransferases have emerged in Gram-negative pathogenic bacteria as an acquired resistance mechanism conferring high-level resistance to all clinically relevant aminoglycosides, even ones that have not yet been released to the market. Since their discovery in 2003, a total of 13 acquired methyltransferases have been identified including three variants. The rate at which these resistance determinants are spreading, combined with the broad resistance profile they confer to most clinically significant aminoglycosides, is jeopardizing the aminoglycosides as a viable last resort antibiotic. Initially, the objectives of the here presented doctoral thesis were to perform a comprehensive in silico analysis of the various families of 16S rRNA methyltransferases, including acquired resistance conferring-, intrinsic resistance conferring- and housekeeping- methyltransferases. The aim of this was to identify a putative origin of the acquired resistance conferring methyltransferases, to potentially discovering their ancestral regulatory mechanism. This study revealed that the acquired 16S methyltransferases most likely convergently evolved from a number of different RNA methyltransferases. Furthermore, this study also demonstrated a high degree of plasticity in the 5' upstream regions between the various acquired resistance conferring methyltransferases, although the region immediately upstream of the coding region was relatively conserved throughout isolate of the same genes. This plasticity is most likely a result of the highly versatile mobile genetic elements in which these acquired resistance determinants are found. |
