Abstract:
Without effective preventive measures, antimicrobial resistance is projected to become the leading cause of death by 2050, resulting in an estimated 10 million deaths annually. Addressing this existential crisis necessitates the development of novel antimicrobial compounds and innovative analytical tools for their identification.
This thesis investigates the total synthesis of the antimicrobial siderophore pulcherriminic acid, which is characterized by a cyclo-dileucine core unit featuring two hydroxamic acids symmetrically positioned within its ring structure. However, the synthetic process did not yield pulcherriminic acid as intended. Instead, two biologically inactive derivatives were produced. These derivatives, despite their structural similarity to pulcherriminic acid, exhibit a shift in the position of core protons due to in situ complexation with sodium.
In addition, novel derivatives of micrococcin P1, the first discovered thiopeptide, were identified during biological investigations of nasal isolates from the human microbiome. Using a combination of high-performance liquid chromatography (HPLC), nuclear magnetic resonance (NMR) spectroscopy, and precursor feeding experiments with labeled threonine, the chemical structures of three previously unknown derivatives were elucidated. The structural analysis revealed depsipeptide-like configurations in all derivatives, marking the first recorded depsipeptide originating from ribosomal biosynthesis. Notably, the loss of antimicrobial activity in these derivatives underscores the critical role of the 2,3-didehydrobutyrine residue.
Furthermore, this thesis describes the development of a novel ion source for mass spectrometry, utilizing low-temperature plasma. This innovation enables the analysis of living microorganisms, such as bacteria, without causing damage. The ion source facilitates multiple analyses of the same living sample, allowing for real-time mass spectrometric monitoring of bacterial growth phases and molecular-level changes over time. Additional capabilities include the in-situ derivatization of analytes and the in-situ separation of molecules under varying pressure gradients.
Synthesis