Biodegradable Broad-Spectrum Antimicrobial Polycarbonates: Investigating the Role of Chemical Structure on Activity and Selectivity

详细信息    查看全文

• 作者：Willy Chin ; Chuan Yang ; Victor Wee Lin Ng ; Yuan Huang ; Junchi Cheng ; Yen Wah Tong ; Daniel J. Coady ; Weimin Fan ; James L. Hedrick ; Yi Yan Yang
• 刊名：Macromolecules
• 出版年：2013
• 出版时间：November 26, 2013
• 年：2013
• 卷：46
• 期：22
• 页码：8797-8807
• 全文大小：539K
• 年卷期：v.46,no.22(November 26, 2013)
• ISSN：1520-5835

文摘

A series of biodegradable polycarbonate polymers was designed and synthesized via organocatalytic ring-opening polymerization of functional cyclic carbonate monomer (MTC鈥揙CH₂BnCl). By adopting a facile postpolymerization functionalization strategy, the polycarbonates were quaternized to yield cationic polymers with quaternary ammonium groups of various pendant structures (e.g., alkyl, aromatic, imidazolinium). The biological properties of these polymers were investigated by microbial growth inhibition assays against clinically relevant Gram-positive and Gram-negative bacteria, fungus as well as hemolysis assays using rat red blood cells. A judicious choice in the structure of the cationic appendages elucidated that the amphiphilic balance of the polymers is a pertinent determinant to render substantial antimicrobial potency and low hemolysis, consequently affording the polymer pButyl_20 (degree of polymerization, 20; quaternary ammonium group, N,N-dimethylbutylammonium) as a highly efficacious and nonhemolytic antimicrobial agent with a remarkable selectivity of more than 1026. To ameliorate the selectivity against a wider spectrum of microbes including the difficult-to-kill Pseudomonas aeruginosa, it was shown that polymers containing N,N-dimethylbutylammonium and N,N-dimethylbenzylammonium groups in 1:1 molar ratio exerted considerable antimicrobial potency while remaining relatively nonhemolytic. Biophysical studies encompassing the determination of water-octanol partition coefficients (log P) and dye leakage studies from model liposomes provided useful insights which delineate the pivotal role of cationic group structure in the antimicrobial activity and mechanism of these polymers. Through field emission scanning electron microscopy (FE-SEM), a physical lysis of microbial cell membranes was deemed operative in the antimicrobial action of these macromolecular agents, which would consequently reduce the propensity toward resistance development. These polymers are envisaged to be promising antimicrobial agents for the prevention and treatment of multidrug-resistant pathogenic infections.