According to estimates by the World Health Organization (WHO), the problem of antibacterial resistance in human medicine is ranked among the leading causes of death in humans. Resistance to antibiotics is mainly promoted by their incorrect and excessive use. Antibiotics that inhibit bacterial growth act bacteriostatically, while others cause the death of bacterial cells and act bactericidally. An important property of the ideal antibiotic is its selective toxicity, which means, it must inhibit only bacterial cells and not harm the host. Antibacterial drugs act according to different mechanisms of action; causing inhibition of cell wall synthesis, forming interactions with the plasma membrane, inhibition of nucleic acid synthesis, inhibition of protein synthesis and inhibition of cellular metabolism. Although several mechanisms of action of antibiotics are known, bacteria are nevertheless capable of developing resistance to them in several different ways. They can limit the antibiotic penetration into the cell, modify cell targets, inactivate the antibiotic, reduce it's concentration in the cell by efflux pumps and form biofilms.
As part of the master's thesis, we used phenotypic screening, which is one of the effective approaches for screening compound libraries, to identify potential new compounds with antibacterial activity. For testing 448 compounds, we used compounds that are part of the compound library of the Faculty of Pharmacy University of Ljubljana and determined their antibacterial activity against six different types of bacteria using the minimum inhibitory concentration. The efficacy of the compounds was tested against three gram-positive bacteria, Staphylococcus aureus, Enterococcus faecium and Enterococcus faecalis, and against the gram-negative bacteria Escherichia coli and its two mutated strains, E. coli D22 and E. coli N43. Of all the tested compounds, 56 (12,5 %) showed biological activity. 13 compounds were active against multiple bacterial species simultaneously. For three compounds, we determined the minimum inhibitory concentration (MIC) value of 15 μmol/L, which was also the lowest determined among all tested compounds samples. The structural analysis of the compounds indicated fragments that could potentially be responsible for antibacterial activity. These include the indane ring, the presence of halogen atoms, and the naphthalene and 8-hydroxyquinoline systems.
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