Design, Synthesis and Evaluation of Macrocyclic Antifungal Peptides

M.P.C. Mulder

    Research output: ThesisDoctoral thesis 1 (Research UU / Graduation UU)

    Abstract

    Fungi are increasingly recognised as major additional pathogens in already critically ill patients. Invasive fungal infections represent a growing threat and over the past two decades the incidence and diversity of fungal infections has increased enormously, especially among immunocompromised patients and patients hospitalized with serious underlying diseases. Resistance against and toxicity of the current antifungal agents underscores the urgent need for development of new antifungal compounds preferentially acting on novel targets. The echinocandins represent the most recent contribution to the arsenal of antifungal compounds that have reached the market in the last decade and act on a novel target. The echinocandins interfere with the synthesis of β-(1,3)-glucan, the major component of the framework of the fungal cell wall, by inhibiting the β-(1,3)-glucan synthase enzyme. They exhibit the most promising pharmacological, and toxicological profiles of the current arsenal of antifungal agents, as 1,3-β-glucan is only found in fungi and not in mammalian cells. As a consequence fewer toxic side effects are observed, as compared to the other classes of antifungal agents. Moreover, the clinically approved agents for this class have rarely shown fungal resistance selection. Despite these advantages, the echinocandin class of compounds has its own limitations. Firstly, due to their semisynthetic nature, they are costly. Secondly their mechanism of action is still unknown. The research described in this Thesis aims at the exploration of the crucial structural features necessary for the antifungal activity of the echinocandin compounds, by synthesizing new derivatives for structure activity studies. This information can be used for the development of improved drugs and may contribute to elucidation of the mode of action.
    Original languageEnglish
    QualificationDoctor of Philosophy
    Awarding Institution
    • Utrecht University
    Supervisors/Advisors
    • Liskamp, R.M.J., Primary supervisor
    • Kruijtzer, John, Co-supervisor
    Award date9 Nov 2012
    Publisher
    Print ISBNs978-94-6182-165-2
    Publication statusPublished - 9 Nov 2012

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