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Title:Requirements and strategies for winning the battle against antibiotic resistance by antisense technology
Author(s):Kotil, Seyfullah Enes
Director of Research:Jakobsson, Eric
Doctoral Committee Chair(s):Jakobsson, Eric
Doctoral Committee Member(s):Blanke, Steven; Sinha, Saurabh; Kuhlman, Thomas; DeVille, Lee
Department / Program:School of Molecular & Cell Bio
Discipline:Biophysics & Computnl Biology
Degree Granting Institution:University of Illinois at Urbana-Champaign
Degree:Ph.D.
Genre:Dissertation
Subject(s):Antibiotic resistance
Evolution of antibiotic resistance
designing antisense molecules
off-target
sustainable therapy
reversing antibiotic resistance
blocking antibiotic resistance
guiding antibiotic resistance
directed evolution
Abstract:In chapter 1 we have investigated the different requirements and conditions for efficiency and specificity of antisense molecules. For specific therapy, an antibacterial RNA must be able to distinguish between its designed targets and its off-targets. This distinction is reflected in the binding energy calculations. The major component of efficiency and specificity is uncovered to be the nature of the off-targets. We have made a new thermodynamic based model to explain in-vivo antisense binding. We have shown that it fits previously unexplained experimental data perfectly. The second chapter deals with how to preserve effective therapy in evolving population. The effectiveness of redesigning on resistance is conditioned on rescuing the hybridization affinity. The hybridization affinity can be rescued if the mutations for acquiring resistance were on the target sequence. However there can be mutations elsewhere in the genome that would confer resistance. We have investigated possible therapy strategies to direct the bacteria to take mutations that are on the target. Having multiple entry mechanisms for RNA therapy seems to be the key to directing bacteria towards a sustainable therapy. Third chapter deals with the following: Using antisense therapy to block progression of antibiotic resistance for trimethoprim. Converge bacteria to desired mutations. Using antisense molecules to induce loss of trimethoprim resistance mutations
Issue Date:2016-12-02
Type:Thesis
URI:http://hdl.handle.net/2142/95600
Rights Information:Copyright 2016, Seyfullah Enes Kotil
Date Available in IDEALS:2017-03-01
Date Deposited:2016-12


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