Beta-lactam antibiotics represent one of the most important classes of antibacterial agents; however, their efficacy is increasingly compromised by the emergence of bacterial resistance and the ability of bacteria to form biofilms. A biofilm is an organized microbial community embedded within an extracellular polymeric matrix, which provides bacteria with enhanced protection against antibiotics and host defense mechanisms. Due to the increasing prevalence of multidrug-resistant Gram-negative bacteria, there is a growing need for the development of novel antibacterial agents with improved activity and the ability to inhibit biofilm formation.
The aim of this master’s thesis was to synthesize novel monobactam derivatives containing triphenylphosphine substituents and to evaluate their antibacterial activity and antibiofilm potential. The study was based on the known properties of aztreonam, which exhibits good activity against Gram-negative bacteria but has limited effects on biofilms. We hypothesized that the introduction of different triphenylphosphine linkers could enhance the interactions of the compounds with the bacterial membrane and consequently influence biofilm development.
In the experimental part, several novel monobactam conjugates with different triphenylphosphine linkers were synthesized. The triphenylphosphine moieties were attached to the aztreonam scaffold either through esterification of the sulfonic acid group or via formation of an amide bond at the carboxyl group. The synthesized compounds were characterized by nuclear magnetic resonance spectroscopy, mass spectrometry, and ultra-highperformance liquid chromatography. Antibacterial activity was evaluated by determining the minimum inhibitory concentrations against various bacterial strains, including Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Acinetobacter baumannii, and Staphylococcus aureus. In addition, the influence of the compounds on bacterial biofilm formation in the Pseudomonas aeruginosa (PAO1) strain was investigated using the crystal violet assay.
The results of antibacterial evaluation differed among the tested bacterial strains. The activity depended on the structural properties of the compounds, particularly on the linker length. In the biofilm assays, some compounds, especially compound number 20 and 18, significantly reduced the extent of biofilm formation. Certain compounds more effectively inhibited the growth of planktonic bacteria (compound 14 S. aureus, compounds 8 and 9 K. pneumoniae, compound 9 P. aeruginosa, compounds 18 and 20 E. coli), whereas others showed a more pronounced effect on biofilm formation.
The obtained results indicate that the synthesized triphenylphosphine monobactam conjugates represent promising lead compounds for the further development of novel agents targeting biofilm-forming Gram-negative bacteria.
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