Amide Moieties Modulate the Antimicrobial Activities of Conjugated Oligoelectrolytes against Gram‐negative Bacteria

Abstract

Cationic conjugated oligoelectrolytes (COEs) are a class of compounds that can be tailored to achieve relevant in vitro antimicrobial properties with relatively low cytotoxicity against mammalian cells. Three distyrylbenzene‐based COEs were designed containing amide functional groups on the side chains. Their properties were compared to two representative COEs with only quaternary ammonium groups. The optimal compound, COE2−3C−C3‐Apropyl, has an antimicrobial efficacy against Escherichia coli with an MIC=2 μg mL−1, even in the presence of human serum albumin low cytotoxicity (IC50=740 μg mL−1) and minimal hemolytic activity. Moreover, we find that amide groups increase interactions between COEs and a bacterial lipid mimic based on calcein leakage assay and allow COEs to readily permeabilize the cytoplasmic membrane of E. coli. These findings suggest that hydrogen bond forming moieties can be further applied in the molecular design of antimicrobial COEs to further improve their selectivity towards bacteria.

Membrane-intercalating conjugated oligoelectrolytes

“…7,60 In the biophysical experiments, antimicrobial MICOEs were also shown to permeabilize liposome membranes which subsequently caused the release of encapsulated calcein. 74 Meanwhile, transcriptomic analysis also supported that membrane disruption is a key MoA because genes related to the membrane stress response were differentially This journal is © The Royal Society of Chemistry 2022 expressed in cells that were exposed to MICOE over a long period of time. 75 Antimicrobial MICOEs usually carry a positive charge, intended to improve the cell affinity toward the negatively charged bacterial membrane.…”

“…59 Recent works by Limwongyut et al also started to consider cytotoxicity and/or haemolytic activities of the MICOEs -both parameters being important in the development of novel drug candidates. 59,74 One MICOE COE2-3C-C4butyl was shown to have a selectivity index with an IC 50 /MIC greater than 256. 59 One explanation is that the mammalian surface is less negatively charged than that of bacteria.…”

“…Currently, the design of new antimicrobial MICOEs relies on a typical material chemistry-based approach by studying one homologous series of molecules. 7,59,74 Inevitably, the structureactivity-relationship (SAR) analysis has become increasingly complex because trends in molecular features became less informative. Hence, a systematic study that integrates both material chemistry and machine learning may help to quickly derive some useful insights to guide the molecular design.…”

Amidine-Based Cationic Conjugated Oligoelectrolytes with Antimicrobial Activity against Pseudomonas aeruginosa Biofilms

“…Previous work shows that the incorporation of amide groups can increase bacterial selectivity, presumably through the ability to form hydrogen bonds with bacterial lipids. 22 Inspiration to further refine the selectivity and increase the activity of COEs was gleaned from the fact that arginine is prevalent in naturally occurring antimicrobial peptides (AMPs). This amino acid residue bears guanidine, a highly basic moiety that is ionized at a physiological pH.…”

“…That the incorporation of hydrogen-bond acceptors in specific domains of COE structures improves antimicrobial activities with no significant increase in cytotoxicity also supports this hypothesis. 22 Due to the high antimicrobial activity and selectivity index of 1b, this compound was therefore selected to be used in subsequent assays throughout this study. An effort to determine the extent of 1b protonation in solution revealed the pK a to be approximately 10.02 (Figures S1 and S2), confirming that most amidine moieties (99.8%) in 1b exist in a protonated form at physiological pH.…”