Login Register Cart 0
Generic placeholder image

Protein & Peptide Letters

Editor-in-Chief

ISSN (Print): 0929-8665
ISSN (Online): 1875-5305

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synthesis and SAR Studies of Antibacterial Peptidyl Derivatives Based upon the Binding Site of Human Cystatin C

Author(s): Maria Dzierżyńska, Emilia Sikorska, Aneta Pogorzelska, Ewa Mulkiewicz, Justyna Sawicka, Dariusz Wyrzykowski, Izabela Małuch, Anders Grubb, Franciszek Kasprzykowski and Sylwia Rodziewicz-Motowidło*

Volume 26, Issue 6, 2019

Page: [423 - 434] Pages: 12

DOI: 10.2174/0929866526666190311162716

Price: $65

Abstract

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.

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.

Keywords: Cystapep 1, antimicrobial activity, peptidomimetics, isothermal, titration calorimetry, NMR structure.

« Previous Next »
Graphical Abstract

[1]
The World Health Organization. Antimicrobial Resistance. Global Report on Surveillance; . 2014.
[2]
De Kraker, M.E.A.; Wolkewitz, M.; Davey, P.G.; Grundmann, H. Clinical impact of antimicrobial resistance in European hospitals: Excess Mortality and length of hospital stay related to methicillin-resistant Staphylococcus aureus bloodstream infections. Antimicrob. Agents Chemother., 2011, 55, 1598-1605.
[3]
The World Health Organization. Monitoring Global Progress on Addressing Antimicrobial Resistance, 2018.
[4]
O’Neill, J. Tackling Drug-Resistant Infections Globally: Final Report And Recommendations - The Review On Antimicrobial Resistance; 2016.
[5]
de Kraker, M.E.A.; Stewardson, A.J.; Harbarth, S. Will 10 million people die a year due to antimicrobial resistance by 2050? PLoS Med., 2016, 13, 1-6.
[6]
Björck, L.; Åkesson, P.; Bohus, M.; Trojnar, J.; Abrahamson, M.; Olafsson, I.; Grubb, A. Bacterial growth blocked by a synthetic peptide based on the structure of a human proteinase inhibitor. Nature, 1989, 337, 385-386.
[7]
Kasprzykowski, F.; Schalén, C.; Kasprzykowska, R.; Jastrzebska, B.; Grubb, A. Synthesis and antibacterial properties of peptidyl derivatives and cyclopeptides structurally based upon the inhibitory centre of human Cystatin C. dissociation of antiproteolytic and antibacterial effects. APMIS, 2000, 108, 473-481.
[8]
Jasir, A.; Kasprzykowski, F.; Kasprzykowska, R.; Lindström, V.; Schalen, C.; Grubb, A. New antimicrobial Cystatin C-based peptide active against gram-positive bacterial pathogens, including methicillin-resistant Staphylococcus aureus and multiresistant coagulase-negative staphylococci. Apmis, 2003, 111, 1004-1010.
[9]
Pikuła, M.; Smużyńska, M.; Krzystyniak, A.; Zieliński, M.; Langa, P.; Deptuła, M.; Schumacher, A.; Łata, J.; Cichorek, M.; Grubb, A.; Trzonkowski, P.; Kasprzykowski, F.; Rodziewicz-Motowidło, S. Cystatin C peptidomimetic derivative with antimicrobial properties as a potential compound against wound infections. Bioorganic. Med. Chem., 2017, 25, 1431-1439.
[10]
White, S.H.; Wimley, W.C.; Selsted, M.E. Structure, function, and membrane integration of defensins. Curr. Opin. Struct. Biol., 1995, 5, 521-527.
[11]
Yeaman, M.R. Mechanisms of antimicrobial peptide action and resistance. Pharmacol. Rev., 2003, 55, 27-55.
[12]
Juszczyk, P.; Kasprzykowska, R.; Kołodziejczyk, A.S. Simple and efficient synthesis of chiral amino alcohols with an amino acid-based skeleton. Lett. Pept. Sci., 2003, 10, 79-82.
[13]
Mulkiewicz, E.; Jastorff, B.; Składanowski, A.C.; Kleszczyński, K.; Stepnowski, P. Evaluation of the acute toxicity of perfluorinated carboxylic acids using eukaryotic cell lines, bacteria and enzymatic assays. Environ. Toxicol. Pharmacol., 2007, 23, 279-285.
[14]
Sikorska, E.; Dawgul, M.; Greber, K.; Iłowska, E.; Pogorzelska, A.; Kamysz, W. Self-assembly and interactions of short antimicrobial cationic lipopeptides with membrane lipids: ITC, FTIR and molecular dynamics studies. Biochim. Biophys. Acta Biomembr., 2014, 1838, 2625-2634.
[15]
Plotnikov, V.; Rochalski, A.; Brandts, M.; Brandts, J.F.; Williston, S.; Frasca, V.; Lin, L. Instrument for studying molecular interactions. Assay Drug Dev. Technol., 2002, 1, 83-91.
[16]
Goddard, T.; Kneller, D. SPARKY 3; , 2001. University of California, San Francisco.
[17]
Case, D.; Babin, V.; Berryman, J.; Betz, R.; Cai, Q.; Cerutti, D.; Cheatham, T.; Darden, T.; Duke, R.; Gohlke, H.; Goetz, A.; Gusarov, S.; Homeyer, N.; Janowski, P.; Kaus, J.; Kolossvary, I.; Kovalenko, A.; Lee, T.; LeGrand, S.; Luchko, T.; Luo, R.; Madej, B.; Merz, K.; Paesani, F.; Roe, D.; Roitberg, A.; Sagui, C.; Salomon-Ferrer, R.; Seabra, G.; Simmerling, C.; Smith, W.; Swails, J.; Walker, R.; Wang, J.; Wolf, R.; Wu, X.; Kollman, P. Amber 14 Reference Manual; , 2014. University of California, San Francisco
[18]
Sikorska, E.; Sobolewski, D.; Kwiatkowska, A. Conformational preferences of proline derivatives incorporated into vasopressin analogues: NMR and molecular modelling studies. Chem. Biol. Drug Des., 2012, 79, 535-547.
[19]
Güntert, P.; Mumenthaler, C.; Wüthrich, K. Torsion Angle Dynamics for NMR Structure Calculation with the New Program DYANA. J. Mol. Biol., 1997, 273, 283-298.
[20]
Nguyen, H.; Roe, D.R.; Simmerling, C. Improved generalized born solvent model parameters for protein simulations. J. Chem. Theory Comput., 2013, 9, 2020-2034.
[21]
Walrant, A.; Correia, I.; Jiao, C.Y.; Lequin, O.; Bent, E.H.; Goasdoué, N.; Lacombe, C.; Chassaing, G.; Sagan, S.; Alves, I.D. Different membrane behaviour and cellular uptake of three basic arginine-rich peptides. Biochim. Biophys. Acta Biomembr., 2011, 1808, 382-393.
[22]
Koradi, R.; Billeter, M.; Wüthrich, K. MOLMOL: A program for display and analysis of molecular structures. J. Mol. Graph., 1996, 14, 51-55.
[23]
Hunter, H.N.; Jing, W.; Schibli, D.J.; Trinh, T.; Park, I.Y.; Kim, S.C.; Vogel, H.J. The Interactions of antimicrobial peptides derived from lysozyme with model membrane systems. Biochim. Biophys. Acta Biomembr., 2005, 1668, 175-189.
[24]
Wenk, M.R.; Seelig, J. Magainin 2 amide interaction with lipid membranes: Calorimetric detection of peptide binding and pore formation. Biochemistry, 1998, 37, 3909-3916.
[25]
Henriksen, J.R.; Andresen, T.L. Thermodynamic profiling of peptide membrane interactions by isothermal titration calorimetry: A search for pores and micelles. Biophys. J., 2011, 101, 100-109.
[26]
Wenk, M.R.; Seelig, J. Vesicle-micelle transformation of phosphatidylcholine / octyl-d-glucopyranoside mixtures as detected with titration calorimetry. J. Phyical Chem., 1997, 101, 5224-5231.
[27]
Kim, J.; Mosior, M.; Chung, L.A.; Wu, H.; McLaughlin, S. Binding of peptides with basic residues to membranes containing acidic phospholipids. Biophys. J., 1991, 60, 135-148.
[28]
Montich, G.; Scarlata, S.; McLaughlin, S.; Lehrmann, R.; Seelig, J. Thermodynamic characterization of the association of small basic peptides with membranes containing acidic lipids. BBA - Biomembr., 1993, 1146, 17-24.
[29]
Schwarzinger, S.; Kroon, G.J.A.; Foss, T.R.; Chung, J.; Wright, P.E.; Dyson, H.J. Sequence-dependent correction of random coil NMR chemical shifts. J. Am. Chem. Soc., 2001, 123, 2970-2978.
[30]
Narang, P.; Bhushan, K.; Bose, S.; Jayaram, B. A computational pathway for bracketing native-like structures fo small alpha helical globular proteins. Phys. Chem. Chem. Phys., 2005, 7, 2364-2375.

Rights & Permissions Print Cite
Article Metrics
22
6
2
© 2024 Bentham Science Publishers | Privacy Policy