Synthesis and SAR studies of antibacterial peptidyl derivatives based upon the binding site of human cystatin C

Maria Dzierżyńska , Emilia Sikorska , Aneta Pogorzelska , Ewa Mulkiewicz , Justyna Sawicka , Dariusz Wyrzykowski , Izabela Małuch , Anders Grubb , Franciszek Kasprzykowski , Sylwia Rodziewicz-Motowidło


Background: Antibacterial peptidyl derivative - Cystapep 1, was previously found to be active both against antibiotic-resistant staphylococci and streptococci as well as antibiotic-susceptible strains of these species. Therefore, it is a promising lead compound to search for new antimicrobial peptidomimetics. Objectives: 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.
Author Maria Dzierżyńska (FCh/DBCh/LMCh)
Maria Dzierżyńska,,
- Laboratory of Medical Chemistry
, Emilia Sikorska (FCh/DOCh/PBSB)
Emilia Sikorska,,
- Pracownia Badań Strukturalnych Biopolimerów
, Aneta Pogorzelska - [Gdanski Uniwersytet Medyczny]
Aneta Pogorzelska,,
- Gdanski Uniwersytet Medyczny
, Ewa Mulkiewicz (FCh/DEA/LChAD)
Ewa Mulkiewicz,,
- Laboratory of Chemical Analytics and Diagnostics
, Justyna Sawicka (FCh/DBCh/LMCh)
Justyna Sawicka,,
- Laboratory of Medical Chemistry
, Dariusz Wyrzykowski (FCh/DGICh/PBChN)
Dariusz Wyrzykowski,,
- Pracownia Biologicznej Chemii Nieorganicznej
, Izabela Małuch (FCh/DOCh/PBSB)
Izabela Małuch,,
- Pracownia Badań Strukturalnych Biopolimerów
, Anders Grubb
Anders Grubb,,
, Franciszek Kasprzykowski (FCh/DBCh/LMCh)
Franciszek Kasprzykowski,,
- Laboratory of Medical Chemistry
, Sylwia Rodziewicz-Motowidło (FCh/DBCh/LMCh)
Sylwia Rodziewicz-Motowidło,,
- Laboratory of Medical Chemistry
Journal seriesProtein and Peptide Letters, ISSN 0929-8665, (N/A 40 pkt)
Issue year2019
Publication size in sheets0.55
Keywords in Englishantimicrobial activity, peptidomimetics, isothermal, titration calorimetry, NMR structure
ASJC Classification2700 General Medicine; 1303 Biochemistry; 1315 Structural Biology
Languageen angielski
Score (nominal)40
Score sourcejournalList
ScoreMinisterial score = 40.0, 07-08-2020, ArticleFromJournal
Publication indicators WoS Citations = 0.000; Scopus Citations = 0.000; Scopus SNIP (Source Normalised Impact per Paper): 2016 = 0.370; WoS Impact Factor: 2018 = 1.168 (2) - 2018=1.065 (5)
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