Dokument: Screening for novel antimicrobial agents and elucidation of the corresponding mechanisms
| Titel: | Screening for novel antimicrobial agents and elucidation of the corresponding mechanisms | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=53934 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20200817-111315-3 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Meier, Dieter [Autor] | |||||||
| Dateien: |
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| Beitragende: | Prof. Dr. Kalscheuer, Rainer [Betreuer/Doktorvater] Prof. Dr. Proksch, Peter [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | Drug resistant pathogens have become a big threat to human health in the past decades since new antimicrobials are rare. Fast resistance evolution is owed to the misuse in healthcare and livestock that has led to the current antimicrobial resistance crisis. The most prevalent drug-resistant bacterial pathogens involved in hospital- and community-associated infections are designated as ESKAPE pathogens and comprise, among others, Staphylococcus aureus and Acinetobacter baumannii.
In chapter 4 of this thesis, different current strategies are reviewed to tackle antibacterial drug resistance including exploration of new antimicrobial sources, targeting subpopulations such as persisters and biofilms, anti-virulence approaches or the use of antimicrobial conjugates and nanocarriers. Chapter 5-7 of this thesis describe my contributions to research on new antimicrobial structures based on three publications. In chapter 5, the plant-derived geranylated chalcone Xanthoangelol was identified to exhibit antibacterial activity against Gram-positive bacteria including Methicillin-resistant Staphylococcus aureus (MRSA) in low micromolar concentration. In this study, we could demonstrate that Xanthoangelol treatment leads to a leakage of intracellular metabolites by affecting bacterial membrane potential and membrane integrity resulting in cell lysis. Treatment with sublethal compound concentrations in Bacillus subtilis revealed indications of cell wall and/or membrane damage and oxidative stress in a proteomic stress profiling approach. In contrast, Xanthoangelol revealed only low hemolytic and cytotoxic effects at higher concentrations. Therefore, Xanthoangelol is a promising antimicrobial lead structure but requires further medicinal chemical optimization before its clinical potential can be assessed. In chapter 6, natural sponge-derived brominated phenoxyphenols were identified with a broad-spectrum activity against Gram-positive and Gram-negative pathogens including the ESKAPE group. Additionally, the phenoxyphenols revealed activity against MRSA subpopulations such as persisters and biofilms. Resistant mutants were isolated harbouring mutations in Phosphotransferase system involved in uptake of sugars. Proteomic stress profiling of sublethally treated cells revealed a strong downregulation of a specific Phosphotransferase component. Additionally, overexpression of this Phosphotransferase component resulted in hypersensitivity VII towards brominated phenoxyphenols. In combination, these findings corroborate the involvement of Phosphotransferase systems in resistance to brominated phenoxyphenols and suggest that these compounds might serve as a surrogate substrate and hijack Phosphotransferase systems to enter the cell. However, while brominated phenoxyphenols are interesting scaffolds to tackle the hard-to-treat MRSA subpopulations and multi-drug resistant Gram-negative bacteria, further investigations are needed to improve their potency and selectivity. Endophytic fungi are a promising source of active compounds. In chapter 7, several active compounds were isolated from the endophytic fungus Didymella sp. IEA-3B.1, originated from leaves of Terminalia catappa (Combretaceae) from Bali, Indonesia. The new compound Didymellanosine and the previously described compound Ascomylactam C showed activity against murine and human cancer cell lines and against Gram-positive pathogens including MRSA, Vancomycin-resistant Enterococcus faecium and Vancomycin-resistant Enterococcus faecalis. Furthermore, both compounds were active against Gram-negative drug-resistant Acinetobacter baumannii in combination with sublethal Colistin concentrations. In contrast, the new compound Didymellanosine was tested on non-malignant human fetal lung fibroblasts MRC5 revealing a 5-6-fold lower cytotoxicity. Due to the increasing emergence of drug-resistant Gram-negative pathogens, Didymellanosine could be a promising lead structure. Nevertheless, further investigations on natural and/or synthetic derivatives are needed to develop congeners with reduced cytotoxicity and improved antimicrobial selectivity. | |||||||
| Lizenz: |  Urheberrechtsschutz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische Biologie und Biotechnologie | |||||||
| Dokument erstellt am: | 17.08.2020 | |||||||
| Dateien geändert am: | 17.08.2020 | |||||||
| Promotionsantrag am: | 23.06.2020 | |||||||
| Datum der Promotion: | 05.08.2020 |
