Novel Antimicrobial Peptide Dendrimers with Amphiphilic Surface and Their Interactions with Phospholipids — Insights from Mass Spectrometry

Molecules

Piotr Polcyn¹  Paulina Zielinska¹  Magdalena Zimnicka¹  Anna Troć¹  Przemysᐪw Kalicki¹  Jolanta Solecka²  Anna Laskowska² 

[1] Institute of Organic Chemistry PAS, Kasprzaka Str. 44/54, Warsaw 01-224, Poland;National Institute of Public Health–National Institute of Hygiene, Chocimska Str. 24, Warsaw 00-791, Poland

关键词: dendrimers;    peptides;    amphiphilic surface;    antimicrobial;    high salt conditions;    circular dichroism;    phospholipids;    ESI-MS;    collision-induced dissociation (CID);   

DOI  :  10.3390/molecules18067120

来源: mdpi

【 摘 要 】

A series of new peptide dendrimers with amphiphilic surface, designed around a dendronized ornithine (Orn) core were synthesized and characterized by ESI-MS, ¹H-, ¹³C- NMR, and CD spectrometry. An improved antimicrobial potency against S. aureus and E. coli was detected as a result of an increased charge, higher branching and variable lipophilicity of the residues located at the C-terminus. Minimal inhibitory concentration (MIC) values indicated that the selected dendrimers were not sensitive to the physiological concentration of Na⁺ and K⁺ ions (100 mM), but expressed reduced potency at 10 mM concentration of Mg²⁺ and Ca²⁺ ions. Circular dichroism (CD) curves measured under various conditions revealed structure and solvent-dependent curve evolution. ESI-MS studies of gas-phase interactions between selected dendrimers and both anionic (DMPG) and neutral (DMPC) phospholipids revealed the presence of variously charged dendrimer/phospholipid aggregates with 1:1 to 1:5 stoichiometry. The collision-induced fragmentation (CID) of the most abundant [dendrimer/phospholipid]²⁺ ions of the 1:1 stoichiometry demonstrated that the studied dendrimers formed stronger complexes with anionic DMPG. Both phospholipids have higher affinity towards dendrimers with a more compact structure. Higher differences in CID energy necessary for dissociation of 50% of the complex formed by dendrimers with DMPG vs. DMPC (∆CID₅₀) correlate with a lower hemotoxicity. Mass spectrometry results suggest that for a particular group of compounds the ∆CID₅₀ might be one of the important factors explaining selectivity of antimicrobial peptides and their branched analogs targeting the bacterial membrane. Both circular dichroism and mass spectrometry studies demonstrated that dendrimers of N^α- and N^ε-series possess a different conformation in solution and different affinity to model phospholipids, what might influence their specific microbicidal mechanism.

【 授权许可】

CC BY   
© 2013 by the authors; licensee MDPI, Basel, Switzerland.