Abstract:
The alarming rise of antimicrobial resistance demands the discovery of novel compounds and mechanisms to combat multidrug-resistant pathogens. In this thesis, three natural products, namely epifadin, cystargolide, and lugdunin, were investigated through chemical synthesis, analytical methods, biological assays, and mechanistic studies.
Epifadin, a highly unstable NRPS-PKS-NRPS hybrid isolated from Staphylococcus epidermidis, was structurally elucidated and shown to have a wide antimicrobial target spectrum while not exhibiting cytotoxicity. Due to its instability under physiological conditions, synthetic efforts focused on developing stable building blocks and epifadin-like derivatives to enable further structure-activity relationship studies.
In addition, N-ethylcystargolides were obtained via semisynthetic modification of natural cystargolides and exhibited enhanced bioactivity compared to their parent compounds. Hemolysis and growth inhibition assays suggested that the improvement results from better cell penetration and ClpP protease inhibition.
Finally, the mode of action of lugdunin was investigated using derivatives synthesized through solid-phase peptide synthesis and a combination of biological, spectroscopic, and computational methods. It was demonstrated that hydrogen bonding is essential for activity and that lugdunin forms peptide nanotubes that translocate protons and ions across bacterial membranes. Moreover, targeted structural modifications enabled lugdunin to penetrate the outer membrane of Gram-negative bacteria, leading to an extended antimicrobial spectrum.
Overall, this thesis provides new insights into three antimicrobial scaffolds and contributes to the development of promising antibiotic candidates.
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