University of Maryland LibrariesDigital Repository at the University of Maryland
    • Login
    View Item 
    •   DRUM
    • Theses and Dissertations from UMD
    • UMD Theses and Dissertations
    • View Item
    •   DRUM
    • Theses and Dissertations from UMD
    • UMD Theses and Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    New molecules to combat the bacterial antibiotic resistance problem

    Thumbnail
    View/Open
    WANG_umd_0117E_12155.pdf (31.64Mb)
    No. of downloads: 222

    Date
    2011
    Author
    WANG, JINGXIN
    Advisor
    Sintim, Herman O
    Metadata
    Show full item record
    Abstract
    Platensimycin/platencin are recently discovered natural products that inhibit membrane formation in bacteria and cyclic diguanylic acid (c-di-GMP) is a master regulator of bacterial biofilm formation. The rise of bacterial antibiotic resistance and the dwindling pipeline of new antibiotics make these molecules of interest to the scientific community. This dissertation reports the design, synthesis and biological evaluation of analogs of platensimycin/platencin and c-di-GMP. Platensimycin and platencin have garnered interest from synthetic chemists due to the complexity of their molecular architecture, coupled with their exciting biological profile (inhibition of bacterial fatty acid synthases). We have developed a concise synthetic approach towards the platensimycin/platencin class of antibiotics. The highlight of our synthesis is the use of dynamic ring-closing metathesis to prepare a bicyclo intermediate and a tandem nucleophilic addition of organolithium to a ketone moiety, followed by a subsequent ring opening of a nearby epoxide to generate complex tricyclic framework. The synthesis of platensimycin or closely related analogs requires multi-steps (average of 17 overall steps). Using a function-oriented synthetic approach, we developed short syntheses of N,N-dialkyl benzoic acid derivatives of platensimycin, and we demonstrate that these readily prepared molecules have comparable antibiotic properties to the difficult-to-synthesize platensimycin/platencin. C-di-GMP has been dubbed the master regulator of bacterial "lifestyle" due to the key role that this molecule plays in bacterial biofilm formation and virulence formation. In order to study c-di-GMP signaling in bacteria, with the ultimate goal of using key insights gained from such studies to develop anti-biofilm or anti-virulence agents, we prepared analogs of c-di-GMP and studied their biophysical and biological profiles. Interestingly, we reveal that conservative modifications to c-di-GMP affect both the biophysical and biochemical properties of this molecule. We also demonstrate a concept called "conformational steering" as a powerful principle to selectively target different classes of receptor proteins that bind to c-di-GMP.
    URI
    http://hdl.handle.net/1903/11713
    Collections
    • Chemistry & Biochemistry Theses and Dissertations
    • UMD Theses and Dissertations

    DRUM is brought to you by the University of Maryland Libraries
    University of Maryland, College Park, MD 20742-7011 (301)314-1328.
    Please send us your comments.
    Web Accessibility
     

     

    Browse

    All of DRUMCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsThis CollectionBy Issue DateAuthorsTitlesSubjects

    My Account

    LoginRegister
    Pages
    About DRUMAbout Download Statistics

    DRUM is brought to you by the University of Maryland Libraries
    University of Maryland, College Park, MD 20742-7011 (301)314-1328.
    Please send us your comments.
    Web Accessibility