Structure–activity relationships of guanylated antimicrobial polymethacrylates

Abstract

Host-defense antimicrobial peptides (AMPs) are a promising lead in the search for novel antibiotics. Many of these peptides exhibit broad-spectrum antibacterial ability, low toxicity toward human cells, and little susceptibility to induction of bacterial resistance. Our research focuses on the development of synthetic polymers that are able to mimic the amphiphilic and cation-rich characteristics of AMPs. This derives bioactive polymers that retain the activity profile of AMPs while utilizing a construct that is less expensive and easier to produce and manipulate chemically. This review details structure-activity relationships (SARs) of a new class of arginine-rich, synthetic AMP mimicking polymers (SAMPs), the guanylated polymethacrylates. These are contrasted with those of amine-based polymers that are mimics of lysine-rich AMPs. The ideal composition for candidates for practical applications was identified as those containing guanidines as a cation source, having a low molecular weight and a low level of lipophilicity. This gave polymers with high potency against Gram-positive strains of bacteria (e.g., Staphylococcus epidermidis MIC = 10 μg/mL) and low toxicity towards human red blood cells ( < 4 % hemolysis at given MIC). This work emphasizes the need to rationalize observed biological activities based not purely on the global lipophilic and cationic character of polymers but rather to consider the profound effect that specific pendant functional groups may have on the potency, selectivity, and mechanisms behind the action of antimicrobial polymers.

ROMP‐ and RAFT‐Based Guanidinium‐Containing Polymers as Scaffolds for Protein Mimic Synthesis

“…These systems also demonstrate cellular internalization, reinforcing the critical importance of guanidinium incorporation. It is important to note that polymeric guanindium methacrylates similar to some molecules studied in this report have also been synthesized by Locock et al., and examined as highly effective antimicrobials …”

“…It is important to note that polymeric guanindium methacrylates similar to some molecules studied in this report have also been synthesized by Locock et al ., and examined as highly effective antimicrobials. [33–36] …”

Antimicrobial Polymers: The Potential Replacement of Existing Antibiotics?

“…Polymer structures and physicochemical properties such as molecular weight, polymer architecture, ratio of amphiphilic and its molecular arrangement are the potential determinants of materials’ antimicrobial potency and selectivity [54]. An ideal amphiphilic antibacterial polymer harboring a cationic arm, low molecular weight and low-level lipophilicity would likely to incur adequate antibacterial activity against Gram-positive bacteria and has minimum hemolysis activity toward human red blood cells i.e., <4% hemolysis at a given minimum inhibitory concentration (MIC) [55]. Nonetheless, Locock et al, 2014 suggested that the combinational effect offered by the specific pendant functional groups may alter the potency, selectivity and mechanisms of synthetic AMP polymers.…”

“…For instance, AMP-mimicking polyurethanes with a lower ratio of hydrophobic region and higher cationic strength conferred the polymers with higher bactericidal activity and lower haemolysis rate [57]. In the comparison of cationic amine- and guanidine-copolymers, the latter of low to moderate molecular weight and hydrophobicity showed higher antimicrobial activity against S. epidermis and lower toxicity toward red blood cells [55]. On the other hand, auto-degradation or biodegradation of polymers is an essential consideration in choosing the right antimicrobial materials [54,58].…”

State-of-the-art polymeric nanoparticles as promising therapeutic tools against human bacterial infections

“…It has been demonstrated that polymer structures as well as their physicochemical properties, such as their molecular arrangement, molecular weight or ratio of amphiphilic composition, are the most important determinants of these materials which significantly compromise their selectivity and antimicrobial potency [ 22 ]. The ideal amphiphilic antibacterial polymer should possess a low molecular weight and low-level of lipophilicity, harbouring a cationic arm to incur adequate antibacterial activity with a minimum haemolysis activity towards red blood cells [ 58 ]. Some studies have demonstrated that AMP-mimicking polyurethanes, with a lower hydrophobic regions and higher cationic strength, show higher bactericidal effect against E. coli with a lower haemolysis grade [ 59 ].…”