Background:
Antibacterial peptidyl derivative - Cystapep 1, was previously found to be
active both against antibiotic-resistant staphylococci and streptococci as well as antibioticsusceptible
strains of these species. Therefore, it is a promising lead compound to search for new
antimicrobial peptidomimetics.
Objective:
We focused on identifying structural elements that are responsible for the biological
activity of Cystapep 1 and its five analogues. We tried to find an answer to the question about the
mechanism of action of the tested compounds. Therefore, we have investigated in details the possibility
of interacting these compounds with biological membrane mimetics.
Methods:
The subject compounds were synthesized in solution, purified and characterized by
HPLC and mass spectrometry. Then, the staphylococci susceptibility tests were performed and their
cytotoxicity was established. The results of Cystapep 1 and its analogues interactions with model
target were examined using the DSC and ITC techniques. At the end the spatial structures of the
tested peptidomimetics using NMR technique were obtained.
Results:
Antimicrobial and cytotoxicity tests show that Cystapep 1 and its peptidomimetic V are
good drug candidates. DSC and ITC studies indicate that disruption of membrane is not the only
possible mechanism of action of Cystapep 1-like compounds. For Cystapep 1 itself, a multi-step
mechanism of interaction with a negatively charged membrane is observed, which indicates other
processes occurring alongside the binding process. The conformational analysis indicated the presence
of a hydrophobic cluster, composed of certain side chains, only in the structures of active peptidomimetics.
This can facilitate the anchoring of the peptidyl derivatives to the bacterial membrane.
Conclusion:
An increase in hydrophobicity of the peptidomimetics improved the antimicrobial
activity against S. aureus, however there is no simple correlation between the biological activity
and the strength of interactions of the peptidyl with bacterial membrane.
Total synthesis of griseusins and elucidation of the griseusin mechanism of action