Dokument: Characterization of the molecular mechanisms underlying the antibacterial activity of natural products
| Titel: | Characterization of the molecular mechanisms underlying the antibacterial activity of natural products | |||||||
| URL für Lesezeichen: | https://docserv.uni-duesseldorf.de/servlets/DocumentServlet?id=72206 | |||||||
| URN (NBN): | urn:nbn:de:hbz:061-20260302-084335-6 | |||||||
| Kollektion: | Dissertationen | |||||||
| Sprache: | Englisch | |||||||
| Dokumententyp: | Wissenschaftliche Abschlussarbeiten » Dissertation | |||||||
| Medientyp: | Text | |||||||
| Autor: | Adeniyi, Emmanuel Tola [Autor] | |||||||
| Dateien: |
| |||||||
| Beitragende: | Prof. Dr. Kalscheuer, Rainer [Gutachter] Kurz, Thomas [Gutachter] | |||||||
| Dewey Dezimal-Klassifikation: | 500 Naturwissenschaften und Mathematik » 570 Biowissenschaften; Biologie | |||||||
| Beschreibung: | The existence and continuity of mankind is threatened by the once heralded miracle drugs losing their effectiveness amidst the growing antibiotic resistance. To alleviate this growing global health crisis, new antibacterial agents addressing novel targets are needed.
This thesis focused on the characterization of the antibacterial activities and mode(s) of action of natural products and nature-inspired compounds. In general, these compounds were screened against a broad range of bacteria, but with a focus on Mycobacterium tuberculosis (Mtb) and Staphylococcus aureus, and their molecular target(s) or mode(s) of action uncovered using a variety of techniques. In the first part, using an optimized Masuda borylation-Suzuki coupling (MBSC) system, natural bisindole alkaloids (hyrtinadine A and alocasin A) known to exhibit diverse bioactivities but lacking antibacterial activity, were modified to generate a library of natural product-derived and synthetic (di)azine-bridged bisindole derivatives. Among these, the 5,5´-chloro front-runner compounds 4j and 4n displayed broad activity against Gram-positive pathogens including methicillin-resistant S. aureus with minimal inhibitory concentrations (MICs) in the sub-micromolar range. Both compounds, while maintaining moderate cytotoxicity against human cell lines, exhibited strong and rapid bactericidal effects and membrane-perturbing features. Their very low propensity for resistance development and potent in vivo efficacy in a mouse wound infection model position them as promising lead structures for antibacterial drug development. In a follow-up study, an optimized MBSC protocol and viability assay were exploited to expand the bisindole compound library with the synthesis and screening of several undescribed N-tosyl bisindole derivatives against MRSA, thus broadening the understanding of the structure-activity relationship of bisindole derivatives beyond halogenation of the indole moieties. In further pursuit of the mode of action of bisindoles, mechanistic studies revealed that these molecules, renamed 5c and 5f, dissipate membrane potential, and permeabilize bacterial membranes by interacting with lipid II and membrane phospholipids, interfering with the lipid II biosynthetic cycle in the process. In the third part, a previously identified anti-tubercular agent, callyaerin, was characterized. Callyaerins are cyclic peptides originally isolated from the Indonesian marine sponge Callyspongia aerizusa. Enabled by solid phase synthesis protocol and viability assay, structure-activity relationship studies of different callyaerins and derivatives uncovered the structural determinants of their anti-tubercular activity, with CalA and CalB being the most potent with minimal inhibitory concentrations (MICs) ranging between 1.56 and 3.13 μM. These cyclic peptides are bacteriostatic in action and selective in activity majorly against Mtb including multidrug and extensively drug-resistant strains, with encouraging cytotoxicity profiles. A combination of mutant screens and chemical proteomics revealed Rv2113, a non-essential, integral membrane protein as the direct target of callyaerins. Further, a deep dive into the proteome of Mtb exposed to callyaerins revealed that these molecules interact with Rv2113, causing a broad downregulation of vital pathways including lipid biosynthesis, cell division, DNA repair, and replication. With excellent activity in an ex vivo infection model, and an unprecedented mode of action differing from all conventional antibiotics, these peptides hold promise for the development of novel tuberculosis drug. | |||||||
| Lizenz: |  Dieses Werk ist lizenziert unter einer Creative Commons Namensnennung 4.0 International Lizenz | |||||||
| Fachbereich / Einrichtung: | Mathematisch- Naturwissenschaftliche Fakultät » WE Pharmazie » Pharmazeutische Biologie und Biotechnologie | |||||||
| Dokument erstellt am: | 02.03.2026 | |||||||
| Dateien geändert am: | 02.03.2026 | |||||||
| Promotionsantrag am: | 14.08.2025 | |||||||
| Datum der Promotion: | 10.12.2025 |
