Development of Selective Ribosome P-Site Inhibitors and Their Applications as New Antitubercular Agents and Efforts Toward Development of First-In-Class Antibiofilm Antibacterial Agents

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Publication Type dissertation
School or College College of Science
Department Chemistry
Author Kanna Reddy, Hariprasada Reddy
Title Development of Selective Ribosome P-Site Inhibitors and Their Applications as New Antitubercular Agents and Efforts Toward Development of First-In-Class Antibiofilm Antibacterial Agents
Date 2017
Description The fight against tuberculosis (TB), has been further complicated by both the emergence of multidrug resistant strains of the organism, along with its coinfection with Human Immunodeficiency Virus (HIV). Since current TB regimens reduce the efficacy of highly active antiretroviral therapies (HAART) by cytochrome induction, TB and HIV cannot be treated simultaneously. With mortality rates of TB-HIV coinfected people rising globally, the scientific community has seen renewed vigor in the search for a novel, noncytochrome inducing antitubercular, agent. In a screen conducted at the University of Utah, the natural product amicetin was identified as a potential scaffold with antitubercular activity, noncytotoxicity, and compatibility with HAART. The first generation of analogs aimed to simultaneously reduce the complexity involved in the synthesis of the disaccharide moiety and replace the acid labile glycosidic linkage. It was shown with analog CZ-02-023 that despite the removal of eight stereocenters from amicetin, potency (IC50 of 0.98 µM against Mtb) and on-target selectivity (SIRR/E.coli =111) could be retained. The crystal structure of Ami bound to the Peptidyl Transferase Center (PTC) of the T. thermophiles 70S ribosome elucidated amicetin's important binding interactions, includes a cation-π interaction of its terminal aminosugar with A2450 and a Watson-Crick base pair between its cytosine portion and G2262. Additionally, hydrogen bonding of amicetin's α-methylserine moiety with the phosphate backbone of G2506 and π-π stacking with the p-aminobenzoyl moiety with A2613 were observed. Not only did this data demonstrate amicetin's binding to the therapeutically unexploited PTC, it served to guide intelligent SAR development that led to the synthesis of CZ-02033 and CZ-02039 with broad spectrum activity and faded on-target selectivity (SIRR/E.coli < 3). The loss of on-target selectivity prompted further modifications to the Cytosine-PABA region in a series of third generation analogs based on the knowledge of the crystal structure of the Ami-70S-tRNA ternary complex. The third generation piperazinyl urea analogs including CZ-02-117, CZ-02118, and CZ-02-132 increased selectivity (SIRR/E.coli >400). Efforts continue to further the development of amicetin-based broad-spectrum antibiotics.
Type Text
Publisher University of Utah
Subject Chemistry; Organic chemistry; Physiology; Microbiology; Medicine; Epidemiology; Public health
Dissertation Name Doctor of Philosophy
Language eng
Rights Management (c) Hariprasada Reddy Kanna Reddy
Format Medium application/pdf
ARK ark:/87278/s6zh1k51
Setname ir_etd
Date Created 2019-10-22
Date Modified 2019-10-22
ID 1469515
Reference URL https://collections.lib.utah.edu/ark:/87278/s6zh1k51
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