Anionic Amphiphilic Dendrimers as Antibacterial Agents

Abstract

An anionic amphiphilic dendrimer is reported that possesses increased cytotoxicological potency against prokaryotic cells compared to eukaryotic cells. The half maximal effective concentration (EC 50 ) for the dendrimer against Bacillus subtilis, a Gram-positive bacterial strain, was measured to be 4.1×10 −5 M, while that against human umbilical vein endothelial cells (HUVEC) was more than 36x greater at a value of 1.5×10 −3 M. EC 50 ratios for two commercial amphiphiles, sodium dodecyl sulfate (SDS) and Triton X-100, in addition to a similar synthesized dendritic structure were at most only 3.8x greater. Furthermore, the observed EC 50 values appear to be correlated to the critical aggregation constant (CAC) in solution suggesting a mechanism of action for these anionic amphiphilic dendrimers related to their supramolecular structures.Dendritic macromolecules, due to their structure, unique properties, and precise compositions, are of significant interest 1 and are finding uses in an ever-increasing number of medical applications. 2 This is especially evident in the drug delivery area where the dendritic structure enables the attachment of a multitude of drugs or targeting moieties as well as the opportunity to control pharmacokinetics through alterations in generation number. 3 Our interest lies in the synthesis and evaluation of dendritic macromolecules composed of building blocks that are natural metabolites or known to be biocompatible for ocular tissue repair, 4 cartilage tissue engineering, 5 and drug delivery. 6 In an ongoing effort to expand the biomedical applications of dendrimers and our understandings of the resulting structure-activity relationships, we are investigating anionic dendritic macromolecules as antibacterial agents. Herein, we report the antibacterial activity of an anionic amphiphilic dendrimer and the striking selectivity in its E-mail: mgrin@bu.edu. There is a significant global need for new antibacterials and alternative mechanisms of action given the rise in resistance among bacteria. 7 Of the various known antibacterial agent classes, amphiphilic compounds act through perturbation and disruption of the prokaryotic membrane. 8 We hypothesized that amphiphilic anionic dendrimers may exhibit antibacterial activity with minimal eukaryotic cell cytotoxicity, since dendrimers with terminal anionic charges are generally non-cytotoxic and have low toxicity in zebrafish whole animal development studies. 9 On the other hand, cationic dendrimers, some of which have antibacterial properties if the positive charge is properly shielded, 10 have repeatedly shown cytotoxicity against a variety of eukaryotic cell lines. 3e,11 In addition, there are many reports of linear polycationic agents but only a few descriptions of linear polyanionic antibacterial agents (e.g., sulfonated polystyrene). 12 Consequently, we synthesized a series of surface-block anionic amphiphilic dendrimers composed of succinic acid, glycerol, and myristic acid possessing various numbers of acid and alkyl functionali...

Towards engineering of self-assembled nanostructures using non-ionic dendritic amphiphiles

“…17 They have been investigated for biomedical applications as nanocarriers for hydrophobic drug molecules, gene therapy etc. [18][19][20][21][22][23][24][25][26][27] However, studies on parameters which influence their self-assembly have not been attempted very much. In general, there are several factors that govern the self-assembly of amphiphiles, for example, hydrophilic-lipophilic balance (HLB), choice of solvent, etc.…”

Scaffold‐Hopping of Multicationic Amphiphiles Yields Three New Classes of Antimicrobials

“…Anionic amphiphiles have been protecting human health since the advent of soaps;e xciting recent developments are represented by polyanionic dendritic structures. [1,2,3] Cationic amphiphiles are likewise of great importance; [4] while nearly every class of living organism employs cationic antimicrobial peptides in ah ost of defensive applications, [5] laboratory-derived quaternary ammonium compounds (QACs) have been used to defend human healthf or about a century. [6,7] QACs have essentially become commodity chemicals, as roughly 500 000 tons of QACs are used every year in a host of consumer products.…”

Dendrimer Structure Diversity and Tailorability as a Way to Fight Infectious Diseases

“…It is noted that the G2 piperazine end-capped dendrimer was the most active. Interesting in its structure was polyanionic ether-based G1 dendrimer with lipophilic core, which was highly active against Gram-positive bacteria-Bacillus subtillis [38]. The noteworthy point is that this dendrimer was found to exhibit low toxicity to healthy human cells.…”