Bacteria are unicellular prokaryotic microorganisms lacking a nucleus that reproduce rapidly, possess high genetic adaptability, the ability to form biofilms, and the capacity to survive in highly diverse environments, which enables their rapid evolution and development of resistance. Due to differences in cellular structure between bacteria and mammalian eukaryotic cells, particularly the presence of a cell wall, differences in ribosomal composition, and the absence of a nucleus, antibacterial agents can selectively act on bacterial structures or processes without significantly harming host cells. Antibacterial agents are a cornerstone of modern medicine; however, their effectiveness is increasingly threatened by the rapid development of bacterial resistance. Among the most problematic representatives of resistant bacteria are the gramnegative bacterium Escherichia coli, which is frequently resistant to β-lactam antibiotics and fluoroquinolones, and the grampositive bacterium Staphylococcus aureus, including methicillin-resistant strains (MRSA), which pose a major challenge in both hospital and community settings. For the above-mentioned reasons, the development of new antibacterial agents is of key importance, and one of the approaches is phenotypic screening of compound libraries, which was also the selected method in this master’s thesis.
Within the framework of this master’s thesis, we performed phenotypic screening of 1,363 compounds that are part of the compound library of the Faculty of Pharmacy University of Ljubljana and evaluated their antibacterial activity against S. aureus and three different strains of E. coli. Of the 247 compounds that demonstrated growth inhibition of at least one of the tested bacteria, 49 of the most promising compounds were selected and their minimum inhibitory concentrations (MICs) were determined. Based on their structure and the obtained results of antibacterial testing, we also attempted to evaluate their potential for further drug development. Among the most promising tested compounds, 31 had previously known antibacterial activity, as they represent variously modified β-lactam derivatives. For these compounds, MIC values were additionally determined against Pseudomonas aeruginosa, Klebsiella pneumoniae, and Acinetobacter baumannii. Among the remaining tested compounds, GDV-30 proved to be the most promising, as it effectively inhibited the growth of all three tested E. coli strains as well as S. aureus. A comparison of the structural characteristics of propargylammonium compounds suggests that they most likely share a common mechanism of action.
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