Polytrimethylenimines: Highly Potent Antibacterial Agents with Activity and Toxicity Modulated by the Polymer Molecular Weight.

Cationic polymers have been extensively investigated as a potential replacement for traditional antibiotics. Here, we examined the effect of molecular weight (MW) on the antimicrobial, cytotoxic, and hemolytic activity of linear polytrimethylenimine (L-PTMI). The results indicate that the biological activity of the polymer sharply increases as MW increases. Thanks to a different position of the antibacterial activity and toxicity thresholds, tuning the MW of PTMI allows one to achieve a therapeutic window between antimicrobial activity and toxicity concentrations. L-PTMI presents significantly higher antimicrobial activity against model microorganisms than linear polyethylenimine (L-PEI) when polymers with a similar number of repeating units are compared. For the derivatives of L-PTMI and L-PEI, obtained through N-monomethylation and partial N,N-dimethylation of linear polyamines, the antimicrobial activity and toxicity were both reduced; however, resulting selectivity indices were higher. Selected materials were tested against clinical isolates of pathogens from the ESKAPE group and Mycobacteria, revealing good antibacterial properties of L-PTMI against antibiotic-resistant strains of Gram-positive and Gram-negative bacteria but limited antibacterial properties against Mycobacteria.

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

The spread of antibiotic-resistant pathogens and the resurgence of tuberculosis disease are major motivations to search for novel antimicrobial agents. Some promising candidates in this respect are cationic polymers, also known as synthetic mimics of antimicrobial peptides (SMAMPs), which act through the membrane-lytic mechanism. Development of resistance toward SMAMPs is less likely than toward currently employed antibiotics; however, further studies are needed to better understand their structure-activity relationship. The main objective of this work is to understand the cross-influence of hydrophobicity, main-chain flexibility, and the topology of ionenes (polycations containing a cationic moiety within the main-chain) on activity. To fulfill this goal, a library of ionenes was developed and compared with previously investigated molecules. The obtained compounds display promising activity against the model microorganisms and drug-resistance clinical isolates, including Mycobacterium tuberculosis. The killing efficiency was also investigated, and results confirm a strong effect of hydrophobicity, revealing higher activity for molecules possessing the flexible linker within the polymer main-chain.

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

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.

Influence of lipid bilayer composition on the activity of antimicrobial quaternary ammonium ionenes, the interplay of intrinsic lipid curvature and polymer hydrophobicity, the role of cardiolipin.

Incorporation of hydrophobic component into amphiphilic polycations structure is frequently accompanied by an increase of antimicrobial activity. There is, however, a group of relatively hydrophilic polycations containing quaternary ammonium moieties along mainchain, ionenes, which also display strong antimicrobial and limited hemolytic properties. In this work, an influence of a hydrophobic side group length on antimicrobial mechanism of action is investigated in a series of novel amphiphilic ionenes. High antimicrobial activity was found by determination of minimum inhibitory concentration (MIC) and minimum bactericidal, and fungicidal concentration (MBC and MFC) in both growth media and a buffer. Biocompatibility was estimated by hemolytic and mammalian cells viability assays. Mechanistic studies were performed using large unilamellar vesicles (LUVs) with different lipid composition, as simplified models of cell membranes. The investigated ionenes are potent and selective antimicrobial molecules displaying a decrease of antimicrobial activity correlated with increase of hydrophobicity. Studies using LUVs revealed that the cardiolipin is an essential component responsible for the lipid bilayer permeabilization by investigated ionens. In contrast to relatively hydrophilic ionenes, more hydrophobic polymers showed an ability to stabilize membranes composed of lipids with negative spontaneous curvature in a certain range of polymer to lipid ratio. The results substantially contribute to the understanding of antimicrobial activity of the investigated class of polymers.

Hydrophilic Quaternary Ammonium Ionenes-Is There an Influence of Backbone Flexibility and Topology on Antibacterial Properties?

The antimicrobial properties of polycations are strongly affected by the structural features such as the backbone flexibility and topology (isomerism) through the polymer ability to attain proper conformation in interaction with the cell membrane. In this paper, a synthesis and biocidal properties evaluation of ionenes characterized by different backbone topology (isomerism) and flexibility are presented. The findings reveal influence of variation in topology on activity against different microorganisms, and general positive effect of improved flexibility. Furthermore, one of the obtained ionenes displays degradable properties in near physiological environment (phosphate-buffered saline pH 7.4, 37 °C). The degradation proceeds via Hofmann elimination reaction and the products are not of acidic character. For the first time a new class of degradable ionenes with a high antimicrobial potential is presented.

High-density polystyrene-grafted silver nanoparticles and their use in the preparation of nanocomposites with antibacterial properties.

The achievement of uniform nanoparticles distribution in polymer matrix is still a major challenge in the design and fabrication of polymer nanocomposites with desired properties. In this paper we propose a novel approach for the preparation of homogeneous polystyrene/silver nanocomposites utilizing Nitroxide Mediated Radical Polymerization (NMRP). In the first step of the developed procedure, the polystyrene grafted silver nanoparticles (Ag@PS) with well-defined core-shell structure and exceptionally high grafting density (from 2 chains/nm2 to 5.9 chains/nm2) have been synthesized through late injection of nitroxide-coated silver nanoparticles (N-AgNPs) into a TEMPOL mediated styrene polymerization system. Afterwards, the synthesized Ag@PS have been used for the preparation of nanocomposites (PS/Ag@PS) by mixing them with narrow-dispersity polystyrenes and thermoforming at 140°C. Due to the high flexibility of polymer chains attached to silver surface through nitroxide linker, free volume effect enables interpenetration of polystyrene molecules that provides excellent mutual miscibility of Ag@PS with polymer matrix. The synthesized nanohybrids (Ag@PS) and their nanocomposites (PS/Ag@PS) exhibit effective antibacterial activity with respect to pathogenic bacteria: Pseudomonas aeruginosa (Gram-negative representative) and Staphylococcus aureus (Gram-positive representative).

Cu-Fe-S Nanocrystals Exhibiting Tunable Localized Surface Plasmon Resonance in the Visible to NIR Spectral Ranges.

Cu-Fe-S nanocrystals exhibiting a strong localized surface plasmon resonance (LSPR) effect were synthesized for the first time. The elaborated reproducible preparation procedure involved copper(II) oleate, iron(III) stearate, and sulfur powder dissolved in oleylamine (OLA) as precursors. The wavelength of the plasmonic resonance maximum could be tuned by changing the Cu/Fe ratio in the resulting nanocrystals, being the most energetic for the 1:1 ratio (486 nm) and undergoing a bathochromic shift to ca. 1200 nm with an increase to 6:1. LSPR could also be observed in nanocrystals prepared from the same metal precursors and sulfur powder dissolved in 1-octadecene (ODE), provided that the sulfur precursor was taken in excess. Detailed analysis of the reaction mixture by chromatographic techniques, supplemented by mass spectrometry and (1)H NMR spectroscopy enabled the identification of the true chemical nature of the sulfur precursor in S/OLA, namely, (C18H35NH3(+))(C18H35NH-S8(-)), a reactive product of the reduction of elemental sulfur by the amine groups of OLA. In the case of the S/ODE precursor, the true precursors are much less reactive primary or secondary thioethers and dialkyl polysulfides.

Solid-phase extraction of explosive nitramines on macroreticular polymers modified by freezing with water or acetone.

A novel approach is proposed to modify the porous structure and surface properties of the polymers used in solid-phase extraction. The approach involves soaking in water or acetone, followed by freezing in liquid nitrogen (77.4 K) and was employed for two polymeric materials: Amberlite XAD-7 and Amberlite XAD-16. Variations in the surface properties of the adsorbents were justified by the action of acetone and water as solvents affecting the textural and other characteristic of the materials. The initial and treated adsorbents were used in extraction of explosive nitramines from aqueous samples. The performed modifications of the polymer texture allow us to increase the recovery rate as compared with the initial adsorbents. The results were justified by the swelling of fragments of the polymers and by the additional process of sorption of nitramines. The results indicate that polymeric adsorbents can be easily modified by the soaking/freezing process and the materials can be achieved that prove usefulness for the effective separation of explosive nitramines from aqueous samples.

Evaluation of adsorption and desorption steps in the solid-phase extraction of explosives using carbon/silica gel nanocomposites.

New series of carbon/silica gel nanocomposites, carbosils, prepared by the carbonization of starch bound to silica gel, and carbosils additionally silylated with octadecyldimethylchlorosilane were synthesized. These materials were applied as adsorbents in the solid-phase extraction of explosive nitrate esters and nitroaromatics from aqueous solutions. The adsorption and desorption steps were evaluated separately. It was found that both the molecular properties of explosives (dipole moments, orbital energies, solvation effects) and textural properties influenced by carbon deposits or octadecyl moieties have a large impact on the recovery rates. It was shown that the composites with moderate content of carbon deposits or with the highest amounts of carbon deposits and additionally silylated can be used as materials tailored for extraction of explosives from the aqueous solutions.

Limits of detection of explosives as determined with IMS and field asymmetric IMS vapour detectors.

Performance of two handheld trace explosives detectors types: SABRE 4000 and MO-2M was compared in terms of the limits of detection determined for: trinitrotoluene, hexahydro-1,3,5-trinitro-1,3,5-triazine, pentaerythritol tetranitrate and nitroglycerin in the particle detection mode. SABRE 4000 detector is a conventional detector based on the ion mobility spectrometry (IMS) and radioactive nickel as the ionization source, whereas in the MO-2M type detector a variant of this technique, viz. the field asymmetric ion mobility spectrometry (FAIMS), and a different ß emitter, tritium, as an ionization source are employed. In determining limits of detection the sampling technique was suggested which resorts to binomial distribution for the determination of the indispensable number of positive measurements required to regard a given amount of explosives detected as reliable. Lower limits of detection were achieved in the study for trinitrotoluene and hexahydro-1,3,5-trinitro-1,3,5-triazine with the MO-2M detector (10- and 100-fold, respectively) than with the SABRE detector, whereas for the remaining two substances limits of detection were identical for either detector. The results obtained were discussed in the aspect of the effect of the detector design, ionization mechanism and volatility of substance as the factors that determine the limits of detection values.