Abstract
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 Nα- and Nε-series possess a different conformation in solution and different affinity to model phospholipids, what might influence their specific microbicidal mechanism.
Highlights
The increasing resistance of microbial pathogens to conventional antibiotics has instigated strong worldwide efforts to develop antimicrobial agents with new structures and mechanism of action.Recently, several types of bactericides with dendrimeric structure have attracted significant attention, providing nanomolecules developed to enable novel therapeutic strategies [1]
We present the divergent method of synthesis of a group of dendrimers 3a–h, built around the core molecules that originate from ornithine (Orn) and contain different residues located at the
Dendrimers were prepared as water soluble hexahydrochlorides that melted within a relatively sharp temperature range when freshly lyophilized
Summary
The increasing resistance of microbial pathogens to conventional antibiotics has instigated strong worldwide efforts to develop antimicrobial agents with new structures and mechanism of action.Recently, several types of bactericides with dendrimeric structure have attracted significant attention, providing nanomolecules developed to enable novel therapeutic strategies [1]. Dendrimers have emerged as a new class of polymers, characterized by branched structure, high monodispersity and a high density of the surface groups These properties encode their most common application as potential drug carriers, gene transfer devices and tools for imaging of biological systems [2]. PAMAMs [3,4] PPIs [5], poly(L-lysine) [6], carbosilane [7] and viologen-phosphorus [8] etc., carrying numerous quaternary amonium or alkylamonium groups at the surface, have been proposed as polycationic microbicides or carriers of antibiotic moieties [9] They express a broad activity against pathogenic Gram-positive and Gram-negative bacteria, targeting mostly bacterial membranes. The chemical versatility of dendrimers provides an opportunity to lower their toxicity and retain bactericidal potential by partial PEG-ylation [11], acetylation [12] or glycosylation [13]
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