University of Illinois Urbana-Champaign

Requirements and strategies for winning the battle against antibiotic resistance by antisense technology

Kotil, Seyfullah Enes

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KOTIL-DISSERTATION-2016.pdf

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https://hdl.handle.net/2142/95600

Description

Title
Requirements and strategies for winning the battle against antibiotic resistance by antisense technology
Author(s)
Kotil, Seyfullah Enes
Issue Date
2016-12-02
Director of Research (if dissertation) or Advisor (if thesis)
Jakobsson, Eric
Doctoral Committee Chair(s)
Jakobsson, Eric
Committee Member(s)
  • Blanke, Steven
  • Sinha, Saurabh
  • Kuhlman, Thomas
  • DeVille, Lee
Department of Study
School of Molecular & Cell Bio
Discipline
Biophysics & Computnl Biology
Degree Granting Institution
University of Illinois at Urbana-Champaign
Degree Name
Ph.D.
Degree Level
Dissertation
Date of Ingest
2017-03-01T17:01:50Z
Keyword(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
Graduation Semester
2016-12
Type of Resource
text
Permalink
http://hdl.handle.net/2142/95600
Copyright and License Information
Copyright 2016, Seyfullah Enes Kotil

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