rdf-syntax-grammar
mods:
  schema location: http://www.loc.gov/mods/v3 http://www.loc.gov/standards/mods/v3/mods-3-2.xsd
  title info:
    title: Structure-based drug mechanism study and inhibitor design targeting tuberculosis
  name:
    name part: Wang, Feng.
    role:
      role term: creator
  name:
    name part: Sacchettini, James C.
    role:
      role term: thesis advisor.
  type of resource: text
  genre: bibliography
  origin info:
    place:
      place term: txu
    date issued: 2010
    issuance: monographic
  language:
    language term: eng
  physical description:
    form: electronic
    form: remote
    extent: 1 online resource.
  abstract: The increase of multi-drug resistant and extensively drug resistant tuberculosis (TB) cases makes it urgent to develop a new generation of TB drugs to counter resistance and shorten treatment. Structural biology, which allows us to "visualize" macromolecules, is now playing a key role in drug discovery. In this work, a structure-based approach was applied to the study of the mode of action of current TB chemotherapies, the identification of potential therapeutic targets, and the design of new inhibitors against TB. Knowledge of the precise mechanisms of action of current TB chemotherapies will provide insights into designing new drugs that can overcome drug-resistant TB cases. Structural biology combined with biochemical and genetic approaches was used to elucidate the mechanisms of actions of isoniazid, ethionamide and prothionamide. The active forms of these anti-TB prodrugs were identified by protein crystallography and the target-inhibitor interactions were revealed by the complex structures. Although these drugs are activated through two completely different routes, they all inhibit InhA, an essential enzyme in mycolic acid biosynthesis, by modification of the enzyme cofactor NAD, which unveils a novel paradigm of drug action. Isoniazid, ethionamide and prothionamide all target InhA, which validates the enzyme as a superb drug target. A structure-based approach was adopted to design new inhibitors targeting InhA, using triclosan as the scaffold. Guided by the InhA-inhibitor complex structures, two groups of triclosan analogs were identified with dramatically increased inhibitory activity against InhA. Structural biology has also provided fundamental knowledge of two potential therapeutic targets, Mtb[beta]-lactamase (BlaC) and fatty-acyl-CoA thioesterase (FcoT). Mtb[beta]-lactamase has been proposed to be the most significant reason for mycobacterial resistance to [beta]-lactam antibiotics. The determination of Mtb BlaC structure not only demonstrates the mecha…
  note: by Feng Wang.
  note: "Major Subject: Chemistry"
  note: Title from author supplied metadata (automated record created 2010-03-12 12:08:51).
  note: Electronic resource.
  note: Doctor of Philosophy Texas A&M University 2007 http://hdl.handle.net/1969.1/ETD-TAMU-1439
  note: Includes bibliographical references.
  note: Text (Dissertation)
  subject:
    topic: Major chemistry
  subject:
    topic: Structure
  subject:
    topic: Drug
  subject:
    topic: tuberculosis
  identifier: http://hdl.handle.net/1969.1/ETD-TAMU-1439
  record info:
    record content source: TXA
    record creation date: 100428
    record change date: 20151201150145.0
    record identifier: in00002581123