Antibacterial agents are compounds that, due to their bactericidal or bacteriostatic activity,
destroy pathogens without harming host cells. Their efficacy is assessed by determining the
minimum inhibitory concentration (MIC) and the minimum bactericidal concentration (MBC).
Antibacterial agents act through different mechanisms. However, the excessive and
inappropriate use of these agents has led to the emergence of bacterial resistance, which poses
a serious threat to public health. Therefore, the discovery and development of new antibacterial
agents is crucial, with compound library screening representing one of the key approaches for
identifying potentially effective new drugs. L,D-transpeptidases have been recognized as a
promising target, as they participate in the peptidoglycan cross-linking and in maintaining the
stability of the bacterial cell envelope, while generally being resistant to classical β-lactam
antibiotics. Their selective inhibition could weaken the cell wall, increase the permeability of
the outer membrane, and facilitate the access of existing antibiotics to their site of action.
As part of the master's thesis, we evaluated and investigated the synergistic activity between
selected antibiotics and specific L,D-transpeptidase inhibitors. In the first phase, we determined
the antibacterial efficacy of selected inhibitors and their binding affinity to the target enzyme.
The research hypothesis was that selective inhibition of L,D-transpeptidases leads to the
weakening of the outer membrane structure, thereby enabling more efficient penetration of
antibiotics to their site of action and thus increasing their effectiveness. The aim of the study
was to identify compounds without intrinsic antibacterial activity that effectively inhibit L,D
transpeptidases. Subsequently, L,D-transpeptidase inhibitors were combined with antibiotics
used in standard treatment, and potential synergistic effects were evaluated. The activity was
defined as synergistic if the addition of the inhibitor resulted in a reduction of the minimum
inhibitory concentration. Tests were conducted on five Escherichia coli strains. The results
showed that the combination of meropenem with L,D-transpeptidase inhibitors exhibited a
synergistic effect, whereas no synergy was observed with the other tested combinations. Based
on this findings, we conclude that, following further optimization, the combination of
meropenem with L,D-transpeptidase inhibitors could represent a promising approach for the
development of new antibacterial agents.
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