Antibiotics represent one of the most important discoveries in modern medicine, as they enable
effective treatment of bacterial infections and have significantly contributed to increased life
expectancy and reduced mortality due to infectious diseases. They are antibacterial agents of
natural or synthetic origin that either kill bacteria or inhibit their growth. Antibiotics differ in
their mechanism of action, spectrum of activity, and chemical structure, with the main groups
including aminoglycosides, macrolides, tetracyclines, quinolones, glycopeptides, sulfonamides,
and β-lactam antibiotics. In recent decades, the emergence of antimicrobial resistance has
become an increasing public health threat. Bacteria can develop antimicrobial resistance through
various mechanisms including enzymatic degradation of antibiotics, alteration of target sites,
reduced membrane permeability, and active efflux of antimicrobial agents. Of particular concern
are β-lactamases, enzymes that hydrolyze β-lactam antibiotics by breaking their characteristic
β-lactam ring. Among β-lactamases, metallo-β-lactamases, constitute a distinct subclass
characterized by dependence on divalent metal ions, most commonly zinc, to mediate hydrolytic
cleavage of the β-lactam ring. To inhibit β-lactamase activity, inhibitors such as clavulanic acid,
sulbactam, and avibactam are used; however, these are only effective against serine βlactamases. A major challenge remains the lack of effective inhibitors against MBLs, as their
structural diversity complicates the development of selective and non-toxic compounds.
In this master’s thesis, we investigated whether any of the selected compounds from the
compound library of the Faculty of Pharmacy, University of Ljubljana, exhibit synergistic
antimicrobial activity in combination with the antibiotic meropenem. Testing was performed on
bacterial strains from the Enterobacteriaceae family, namely Escherichia coli and Salmonella,
expressing metallo-β-lactamases. First, the antibacterial activity of individual compounds was
assessed, and their minimum inhibitory concentration were determinated. According to
EUCAST guidelines for 2025, the clinical susceptibility breakpoint for meropenem in
Enterobacteriaceae is ≤ 2 µg/mL, while values above 8 µg/mL indicate resistance. Among the
88 tested combinations, weak synergistic activity with meropenem was observed for compounds
MBL-3, MBL-14, MBL-17, MBL-35, and MBL-39.
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