Access Type

Open Access Embargo

Date of Award

January 2017

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

David Crich

Abstract

The ever-growing bacterial resistance to existing antibiotics is alarming to humanity. Many researchers decided to revisit aminoglycosides with renewed emphasis on chemical modification as they have long been used as highly potent antibiotics for treating severe bacterial infections. The bactericidal effect of aminoglycosides is mainly due to protein synthesis inhibition by binding to the A-site of the bacterial ribosomes. However, the high potency and the broad spectrum of aminoglycosides has been outweighed by their side effects, especially ototoxicity, and by the resistance of pathogens. The goal of this research was the modification of existing aminoglycosides to develop derivatives which are less toxic and that evade resistance. The chapters in the thesis discuss the chemical synthesis as well as the biological evaluation of the newly synthesized analogs. This study has focused on the modification of aminoglycosides netilmicin and apramycin.

Chapter one introduces the MDR bacterial infection problem and its influence. Chapter one also introduces the aminoglycosides elaborating their history, classifications, and their mechanism of action. The resistance mechanisms against aminoglycosides and their adverse effects, as well as the ways to prevent them are briefly explained.

Chapter two discusses modifications of netilmicin at the 4’-position conducted with a view to reducing the ototoxicity but not the antibiotic activity, as was previously done in the 4,5-series with paromomycin. The antibacterial activity and antiribosomal activity of the six netilmicin derivatives synthesized were determined. The 4’-position is more sensitive to modification in 4,6-series than in the 4,5-series to the extent that such modifications are ineffective. Chapter two also highlights the use of phenyl triazenes as selective protecting groups for secondary amines in the presence of primary amines. Several polyamine substrates were selectively protected as phenyl triazenes, and primary amines were subsequently protected as azides, benzyloxy carbamates, or fluorenylmethyl carbamates. Phenyl triazenes enabled the synthesis of plazomicin, an aminoglycoside in phase III clinical trials, in fewer steps and higher yield than previously reported.

Chapter three describes derivatization and modification of apramycin at the 5-position. The influence of these modifications was investigated using cell-free translation assays and antibacterial assays. An apramycin-paromomycin hybrid was synthesized with the aim of combining paromomycin’s high activity with apramycin’s low ototoxicity. Eighteen compounds were synthesized with modifications mainly at the 5-position leading to the development of a potent derivative that was more active than apramycin against all bacterial strains tested and which also showed better ribosomal selectivity. This investigation affords proof of concept for the development of more potent and selective aminoglycosides in the apramycin class.

Available for download on Thursday, November 22, 2018

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