Influence of PEG Subunit on the Biological Activity of Ionenes: Synthesis of Novel Polycations, Antimicrobial and Toxicity Studies

Abstract

An alarming increase of antibiotic resistance among pathogens creates an urgent need to develop new antimicrobial agents. Many reported polycations show high antimicrobial activity along with low hemolytic activity. Unfortunately, most of those molecules remain highly cytotoxic against various mammalian cells. In this work, a systematic study on the impact of triethylene glycol monomethyl ether side groups (short polyethylene glycol (PEG) analog) on antimicrobial, hemolytic, and cytotoxic properties of novel amphiphilic ionenes is presented. A detailed description of synthesis, leading to well‐defined alternating polymers, which differ in structural elements responsible for hydrophilicity (PEG) and hydrophobicity (alkyl chain), is presented. Obtained results show that the PEG moiety and fine‐tuned hydrophilic‐lipophilic balance of ionenes synergistically lead to low cytotoxic, low hemolytic molecules with high activity against S. aureus, including methicillin‐resistant strains (MRSA). Additionally, the results of mechanistic studies on bacterial cells and fluorescently labeled liposomes are also discussed.

Main-chain flexibility and hydrophobicity of ionenes strongly impact their antimicrobial activity: an extended study on drug resistance strains and Mycobacterium

“…Zeta-potential measurements indicated a relatively high positive electrokinetic charge on the surface of the aggregates, which is higher for the more exible TMEDA-containing ionenes and for the meta isomers in comparison to the para ones. 3 along with the previously reported 31,53,54 MIC values for Cn-D-m and Cn-T-p polymers. Results display a wide range of activity levels among the studied ionenes, from highly potent (MIC 2-8 mg mL À1 ) to relatively weak (MIC 128-256 mg mL À1 ).…”

“…Data collected for the C n -D-p and C n -T-m polymers are presented in Fig. 3 along with the previously reported 31,53,54 MIC values for C n -D-m and C n -T-p polymers. Results display a wide range of activity levels among the studied ionenes, from highly potent (MIC 2–8 μg mL −1 ) to relatively weak (MIC 128–256 μg mL −1 ).…”

“…Ionenes from the series Cn-D-m and Cn-T-p, and ionene C0-T-m, were obtained and characterized in previously published works. 31,53,54 The synthesis and characterization of the exible meta-ionenes (Cn-T-m) and rigid para-ionenes (Cn-D-p) are presented herein for the rst time. To obtain the desired polycations monomers, 1-Cn, 2, and 3 were synthesized according to Schemes 1 and S1.…”

“…To investigate the cross-inuence of the hydrophobicity, mainchain exibility, and topology of ionenes on their antimicrobial and hemolytic activity, a library of ionenes composed of newly synthesized molecules and already reported structures 31,53,54 was used (Fig. 1a).…”

“…The fast killing kinetics of the presented ionenes prove their contact mechanism of action, which was previously investigated for this class of polycations in other works. 36,53,54…”