Access Type

Open Access Embargo

Date of Award

January 2018

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry

First Advisor

David Crich

Abstract

ABSTRACT

MODIFICATION OF 4,5- AMINOGLYCOSIDES TO OVERCOME DRUG RESISTANCE BACTERIA AND TOXIC SIDE EFFECT

by

Guanyu Yang

September 2018

Advisor: Professor David Crich

Major: Chemistry

Degree: Doctor of Philosophy

Infectious diseases causing by antibiotic resistant pathogen are one of the major threat to human health and society today. Many researchers tried to develop next generation of antibiotics by reinvesting the existing antibacterial drugs. Aminoglycosides have long been used as highly potent and broad-spectrum antibiotics for treating bacterial infections. But their side effect, especially the irreversible ototoxicity, and the fast-growing resistant problem limit their application. The goal of this research was to develop next generation of AGAs that are less toxic and resistance-proof by modifying known aminoglycosides.

Chapter one briefly explains the MDR bacterial infection problem and its influence. Aminoglycosides are also well discussed in this chapter, including their history, classifications, mechanism of action, toxicity and resistance problems, as well as the recent research advances.

Chapter two discusses the synthesis and biological evaluation of 6’-deshydroxymethyl paromomycin The loss of activity shows in the biological test suggested that the 6'-deshydroxymethyl modification was not an effective modification.

Chapter three discusses the 3’-deoxy modification on different 4,5-AGAs. A novel synthetic method utilizing samarium iodide reduction to achieve 3’-deoxygenation modification is introduced. This new method shows good substrate compatibility and avoids the tedious scheme in the traditional method. The 3’-deoxy 4,5-AGAs retain their antibacterial activity and exhibit activity against some AGA resistance strains. But they still suffers from APH(3’,5’’) resistance mechanism.

Chapter four describes the synthesis and biological test results of the 3’,5’’-dideoxy-5’’-formamido paromomycin. The synthesis of this doubly modified compound demonstrates the wide application potency of the samarium iodide reduction for 3’-deoxy modification. The biological experiment results show that the doubly modified compound has good antibacterial activity even in the presence of some common AMEs.

Chapter five discussed the synthesis and biological evaluation of a triply modified paromomycin derivative. The combination of 3’-deoxy, 4’-deoxy-4’-C-propyl and 5’’-deoxy-5’’-formamido modification into paromomycin leads to unexpected loss of antiribosomal and antibacterial activity.

Finally, chapter six documents the experiment procedure and characterization data for the synthesized compounds and chapter seven presents the overall conclusion.

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