Biobased polymers derived from itaconic acid bearing clickable groups with potent antibacterial activity and negligible hemolytic activity.

Herein, we report, for the first time, the synthesis of clickable polymers derived from biobased itaconic acid, which was then used for the preparation of novel cationic polymers with antibacterial properties and low hemotoxicity via click chemistry. Itaconic acid (IA) was subjected to chemical modification by incorporating clickable alkyne groups on the carboxylic acids. The resulting monomer with pendant alkyne groups was easily polymerized and copolymerized with dimethyl itaconate (DMI) by radical polymerization. The feed molar ratio of comonomers was varied to precisely tune the content of alkyne groups in the copolymers and the amphiphilic balance. Subsequently, an azide with a thiazole group, which is a component of the vitamin thiamine (B1), was attached onto the polymers by copper-catalyzed azidealkyne cycloaddition (CuAAC) click chemistry leading to triazole linkages. N-Alkylation reactions of the thiazole and triazole groups with methyl and butyl iodides provide the corresponding itaconate derivatives with pendant azolium groups. The copolymers with variable cationic charge densities and hydrophobic/ hydrophilic balances, depending on the comonomer feed ratio, display potent antibacterial activity against Gram-positive bacteria, whereas the activity was almost null against Gram-negative bacteria. Hemotoxicity assays demonstrated that the copolymers exhibited negligible hemolysis and excellent selectivity, more than 1000-fold, for Gram-positive bacteria over human red blood cells.post-print1945 K

Antimicrobial polymethacrylates based on quaternized 1,3-thiazole and 1,2,3-triazole side-chain groups

Polymers containing quaternary ammonium cations (QUATS) are well-known antimicrobial and disinfectant agents. Mono- and bis-heterocyclic methacrylate monomers (MTAs) and their corresponding polymers (PMTAs) bearing 1,3-thiazole and 1,2,3-triazole groups with different spacer groups were designed, inspired by azole heterocycles found in nature. PMTAs were obtained by a simple synthetic approach from alkynyl alcohols and a thiazole azide derivative, followed by conventional radical polymerization. The N-alkylation of azole rings allowed the preparation of mono and dicationic polyelectrolytes (PMTAs-RI) with different amphiphilic natures. The resulting antimicrobial properties towards different microorganisms, bacteria and fungi, which are the cause of healthcare-associated infections, as well as their hemotoxic action using human blood red cells (RBCs) are reported. The results demonstrate that methyl and butyl quaternized PMTAs present a highly selective toxicity against microorganisms because they are non-hemolytic (some of them with selectivity values higher than 1000). In contrast, longer N-alkyl analogs lead to a reduction in antimicrobial activity, showing a general structure-activity relationship that depends on the amphiphilic balance of the polycation. These polymeric families may provide a scope for developing a new class of versatile antimicrobial QUATS with promising biomedical applications. This journal isPeer Reviewe

High efficiency antimicrobial thiazolium and triazolium side-chain polymethacrylates obtained by controlled alkylation of the corresponding azole derivatives

Two series of antimicrobial polymethacrylates (PMTAs) bearing mono and bis-cationic quaternary ammonium cations (QUATs) were prepared by controlled N-alkylation of 1,3-thiazole and 1,2,3-triazole pendant groups with butyl iodide (PMTAs-BuI). The degree of quaternization (DQ) of the azole heterocycles was monitored by 1H NMR spectroscopy over a wide range of reaction times. Spectra analysis of the 1H NMR aromatic region allowed to characterize and quantify the different species involved and, therefore, to control the chemical composition distribution of the amphiphilic polycations. The polymer charge density and the hydrodynamic sizes were measured by zeta potential and dynamic light scattering (DLS), respectively. Consequently, the relationship between structure and antibacterial properties and toxicity was studied. Interestingly, these polyelectrolytes present excellent selective toxicity against bacteria being nonhemolytic even at low values of DQ. Furthermore, they were also evaluated for their microbial time-killing efficiency, presenting a 3 log-reduction in only 15 min. Additionally, the bacteria cell morphology treated with PMTAs-BuI was analyzed.Peer Reviewe

Antibacterial Polymers Based on Poly(2-hydroxyethyl methacrylate) and Thiazolium Groups with Hydrolytically Labile Linkages Leading to Inactive and Low Cytotoxic Compounds

Herein, we develop a well-defined antibacterial polymer based on poly(2-hydroxyethyl methacrylate) (PHEMA) and a derivative of vitamin B1, easily degradable into inactive and bio- compatible compounds. Hence, thiazole moiety was attached to HEMA monomer through a car- bonate pH-sensitive linkage and the resulting monomer was polymerized via reversible addition- fragmentation chain transfer (RAFT) polymerization. N-alkylation reaction of the thiazole groups leads to cationic polymer with thiazolium groups. This polymer exhibits excellent antibacterial activity against methicillin-resistant Staphylococcus aureus (MRSA) with an MIC value of 78 μg mL−1, whereas its degradation product, thiazolium small molecule, was found to be inactive. Hemotoxicity studies confirm the negligible cytotoxicity of the degradation product in comparison with the original antibacterial polymer. The degradation of the polymer at physiological pH was found to be progres- sive and slow, thus the cationic polymer is expected to maintain its antibacterial characteristics at physiological conditions for a relative long period of time before its degradation. This degradation minimizes antimicrobial pollution in the environment and side effects in the body after eradicating bacterial infection.This work was funded by the MICINN (PID2019-104600RB-I00), the Agencia Estatal de Investigación (AEI, Spain) and Fondo Europeo de Desarrollo Regional (FEDER, E

Hemolytic and Antimicrobial Activities of a Series of Cationic Amphiphilic Copolymers Comprised of Same Centered Comonomers with Thiazole Moieties and Polyethylene Glycol Derivatives

© 2020 by the authors.A series of well-defined antimicrobial polymers composed of comonomers bearing thiazole ring (2-(((2-(4-methylthiazol-5-yl)ethoxy)carbonyl)oxy)ethyl methacrylate monomer (MTZ)) and non-hemotoxic poly(ethylene glycol) side chains (poly(ethylene glycol) methyl ether methacrylate (PEGMA)) were synthesized by reversible addition-fragmentation chain transfer (RAFT) polymerization. By post-polymerization functionalization strategy, polymers were quaternized with either butyl or octyl iodides to result in cationic amphiphilic copolymers incorporating thiazolium groups, thus with variable hydrophobic/hydrophilic balance associated to the length of the alkylating agent. Likewise, the molar percentage of PEGMA was modulated in the copolymers, also affecting the amphiphilicity. The antimicrobial activities of these cationic polymers were determined against Gram-positive and Gram-negative bacteria and fungi. Minimum inhibitory concentration (MIC) was found to be dependent on both length of the alkyl hydrophobic chain and the content of PEGMA in the copolymers. More hydrophobic octylated copolymers were found to be more effective against all tested microorganisms. The incorporation of non-ionic hydrophilic units, PEGMA, reduces the hydrophobicity of the system and the activity is markedly reduced. This effect is dramatic in the case of butylated copolymers, in which the hydrophobic/hydrophilic balance is highly affected. The hemolytic properties of polymers analyzed against human red blood cells were greatly affected by the hydrophobic/hydrophilic balance of the copolymers and the content of PEGMA, which drastically reduces the hemotoxicity. The copolymers containing longer hydrophobic chain, octyl, are much more hemotoxic than their corresponding butylated copolymers.This research was funded by MINECO, Project MAT2016-78437-R, the Agencia Estatal de Investigación (AEI, Spain), and Fondo Europeo de Desarrollo Regional (FEDER, EU).Peer reviewe

Tailoring macromolecular structure of cationic polymers towards efficient contact active antimicrobial surfaces

The aim of this work is the preparation of contact active antimicrobial films by blending copolymers with quaternary ammonium salts and polyacrylonitrile as matrix material. A series of copolymers based on acrylonitrile and methacrylic monomers with quaternizable groups were designed with the purpose of investigating the influence of their chemical and structural characteristics on the antimicrobial activity of these surfaces. The biocide activity of these systems was studied against different microorganisms, such as the Gram-positive bacteria Staphylococcus aureus and the Gram-negative bacteria Pseudomona aeruginosa and the yeast Candida parapsilosis. The results confirmed that parameters such as flexibility and polarity of the antimicrobial polymers immobilized on the surfaces strongly affect the efficiency against microorganisms. In contrast to the behavior of copolymers in water solution, when they are tethered to the surface, the active cationic groups are less accessible and then, the mobility of the side chain is critical for a good contact with the microorganism. Blend films composed of copolymers with high positive charge density and chain mobility present up to a more than 99.999% killing efficiency against the studied microorganisms.This work was supported financially by the MINECO (Project MAT2016-78437-R), the Agencia Estatal de Investigación (AEI, Spain) and Fondo Europeo de Desarrollo Regional (FEDER, EU).Peer Reviewe

Antibacterial and compostable polymers derived from biobased itaconic acid as environmentally friendly additives for biopolymers

In this work, a series of antibacterial cationic copolymers derived from bio-sourced itaconic acid was studied as potential biobased active components in biodegradable formulations based on poly(butylene adipate-co-terephthalate) (PBAT) for packaging applications. These copolymers were first characterized by testing their antimicrobial activity against resistant bacterial strains, their biodegradability in compost conditions, and their thermal properties by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The antibacterial properties showed potent activity against Methicillin-resistant Staphylococcus aureus (MRSA), with MIC values as low as 78 μg mL. Related to their biodegradability, the cationic polymers biodegraded fast under compost conditions and even a priming effect was observed in the compost. Thermal properties, characterized by DSC and TGA, showed that the copolymers thermally degraded at temperature relatively low; nevertheless, they are able to be processed at temperatures up to ∼150 °C. Subsequently, these antibacterial polymers were successfully blended as minor active component (10 wt%) with PBAT by melt-extrusion and press-compression molding. The resulting biopolymeric films exhibit potent antibacterial activity, which confirm that the cationic polymers incorporated as active component are able to perverse this activity after the processing and impart antibacterial properties to PBAT bioplastic. Therefore, these antibacterial biobased polymers derived from itaconic acid seem to be good candidates for applications related to active food packaging or even for biomedical devices.This work was funded by the MICINN (PID2019-104600RB-I00), the Agencia Estatal de Investigación (AEI, Spain) and Fondo Europeo de Desarrollo Regional (FEDER, EU) and by CSIC (LINKA20364). A. Chi- loeches acknowledges MICIU for his FPU fellowship FPU18/017

Adhesive antibacterial coatings based on copolymers bearing thiazolium cationic groups and catechol moieties as robust anchors

Herein, we describe a simple approach for the preparation of antibacterial polymeric coatings based on mussel inspired catechol chemistry. A series of statistical copolymers composed of 2-(4-methylthiazol-5-yl)ethyl methacrylate (MTA) and N-(3,4-dihydroxyphenethyl) methacrylamide (DOMA) were synthesized by conventional free radical and reversible addition fragmentation chain transfer (RAFT) polymerizations. Subsequently, the thiazole groups of MTA units were quatemized with methyl and butyl iodide as alkylating agents to provide cationic copolymers with also adhesive anchoring groups of catechol. The copolymers were systematically studied to investigate the effects of composition (MTA/DOMA ratio), molecular weight and alkylating agent on adhesive and antibacterial properties. It was proved that DOMA units play a major role in the adhesion, while the antibacterial activity only decreases slightly with content of DOMA up to 32%. Remarkable, for similar MTA molar equivalent, the copolymers with higher molecular weight exhibit better antimicrobial properties in solution, whereas when they are tethered onto a surface as a coating, the copolymers with lower molecular weight showed enhanced antibacterial performance even against Gram-negative bacteria. These findings confirm that antimicrobial polymers attached onto surfaces behave in a different manner than in solution, and can be more effective as the mobility and accessibility of the cationic groups increase.Web of Science136art. no. UNSP 10527