Dokument: Functional characterization of the antimicrobial activity of synthetic callyaerins against Mycobacterium tuberculosis

Titel:	Functional characterization of the antimicrobial activity of synthetic callyaerins against Mycobacterium tuberculosis
URL für Lesezeichen:	https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=53376
URN (NBN):	urn:nbn:de:hbz:061-20210623-091227-9
Kollektion:	Dissertationen
Sprache:	Englisch
Dokumententyp:	Wissenschaftliche Abschlussarbeiten » Dissertation
Medientyp:	Text
Autor:	Gröner, Yvonne [Autor]
Dateien:	[Dateien anzeigen] Adobe PDF [Details] 7,11 MB in einer Datei [ZIP-Datei erzeugen] Dateien vom 05.06.2020 / geändert 05.06.2020
Beitragende:	Prof. Dr. Kalscheuer, Rainer [Betreuer/Doktorvater] Prof. Dr. Proksch, Peter [Gutachter]
Dewey Dezimal-Klassifikation:	500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie
Beschreibung:	Tuberculosis (TB), caused by Mycobacterium tuberculosis (M. tuberculosis), is still one of the top ten causes of deaths worldwide. With 1.4 million deaths in 2018, TB is the leading cause of deaths from a single infectious pathogen. Drug resistance of M. tuberculosis represents a major challenge. In the last decades, extensively drug resistant and totally drug-resistant phenotypes have emerged that nearly leave no treatment opportunities. This situation is exacerbated by the hesitance and diffidence in the development of new drugs. To control the global spread of TB, new drugs are urgently needed. Nature and its magnitude of products represent a rich source of new active compounds, underlined by a long history as antibiotics. Among the different classes of natural products, cyclic peptides stick out due to their three-dimensional structure, resulting in strong interaction with their molecular targets. Furthermore, cyclic peptides are relatively easy to synthesize overcoming the problem of product availability of many other natural products. In this study, a library of synthetic cyclic peptides belonging to the callyaerin family was investigated to elucidate their selective growth inhibiting activity against M. tuberculosis. Besides revealing the indispensability of the cyclic structure, the bulky hydrophobic chemical properties of callyaerins were found to be essential for their activity. The strong growth inhibition of M. tuberculosis in low micromolar concentrations combined with a lack of cytotoxic side effects qualify callyaerins as new drug leads. By application of an affinity enrichment approach employing biotinylated callyaerins, hypoxic response protein 1 (Hrp1), a protein involved in bacterial dormancy, was identified as an interaction partner. Following contact with Hrp1, a protein cascade might be triggered resulting in reduced metabolism and suppressed replication of the bacteria and thereby causing a bacteriostatic effect of callyaerins. Furthermore, the membrane protein Rv2113 was identified as an essential determinant of activity and resistance, likely mediating cell wall permeation of callyaerins in M. tuberculosis. Heterologous expression of this membrane protein in other mycobacteria led to a strong sensitization against callyaerins. Rv2113 therefore might be exploited as a potential carrier system for callyaerin conjugates with compounds that otherwise fail to pass the complex cell wall structure of M. tuberculosis. In a proof of principle experiment, the exceptional selective activity of a fluorescent Cy3_CalA conjugate substantiated the capability of extending the callyaerin core structure with bulky moieties without impairing activity, paving the way for the design of multi-targeting pharmacophores. This study shows that callyaerins are not only interesting new drug leads, but are also employable in further fields of application helping to embank the global spread of TB.
Lizenz:	Urheberrechtsschutz
Fachbereich / Einrichtung:	Mathematisch- Naturwissenschaftliche Fakultät
Dokument erstellt am:	23.06.2021
Dateien geändert am:	23.06.2021
Promotionsantrag am:	05.03.2020
Datum der Promotion:	27.05.2020