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Nitric oxide-releasing dendrimers as antibacterial agents.

ABSTRACT: The antibacterial activity of a series of nitric oxide (NO)-releasing poly(propylene imine) (PPI) dendrimers was evaluated against both Gram-positive and Gram-negative pathogenic bacteria, including methicillin-resistant Staphylococcus aureus . A direct comparison of the bactericidal efficacy between NO-releasing and control PPI dendrimers (i.e., non-NO-releasing) revealed both enhanced biocidal action of NO-releasing dendrimers and reduced toxicity against mammalian fibroblast cells. Antibacterial activity for the NO donor-functionalized PPI dendrimers was shown to be a function of both dendrimer size (molecular weight) and exterior functionality. In addition to minimal toxicity against fibroblasts, NO-releasing PPI dendrimers modified with styrene oxide exhibited the greatest biocidal activity (≥99.999% killing) against all bacterial strains tested. The N-diazeniumdiolate NO donor-functionalized PPI dendrimers presented in this study hold promise as effective NO-based therapeutics for combating bacterial infections.

SUBMITTER: Sun B

PROVIDER: S-EPMC3482834 | biostudies-literature | 2012 Oct

REPOSITORIES: biostudies-literature

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Nitric oxide-releasing dendrimers as antibacterial agents.

Sun Bin B Slomberg Danielle L DL Chudasama Shalini L SL Lu Yuan Y Schoenfisch Mark H MH

Biomacromolecules 20120926 10

The antibacterial activity of a series of nitric oxide (NO)-releasing poly(propylene imine) (PPI) dendrimers was evaluated against both Gram-positive and Gram-negative pathogenic bacteria, including methicillin-resistant Staphylococcus aureus . A direct comparison of the bactericidal efficacy between NO-releasing and control PPI dendrimers (i.e., non-NO-releasing) revealed both enhanced biocidal action of NO-releasing dendrimers and reduced toxicity against mammalian fibroblast cells. Antibacte ...[more]

PMID: 23013537

Similar Datasets

Nitric oxide-releasing amphiphilic poly(amidoamine) (PAMAM) dendrimers as antibacterial agents.

Project description:A series of amphiphilic nitric oxide (NO)-releasing poly(amidoamine) (PAMAM) dendrimers with different exterior functionalities were synthesized by a ring-opening reaction between primary amines on the dendrimer and propylene oxide (PO), 1,2-epoxy-9-decene (ED), or a ratio of the two, followed by reaction with NO at 10 atm to produce N-diazeniumdiolate-modified scaffolds with a total storage of ~1 μmol/mg. The hydrophobicity of the exterior functionality was tuned by varying the ratio of PO and ED grafted onto the dendrimers. The bactericidal efficacy of these NO-releasing vehicles against established Gram-negative Pseudomonas aeruginosa biofilms was then evaluated as a function of dendrimer exterior hydrophobicity (i.e., ratio of PO/ED), size (i.e., generation), and NO release. Both the size and exterior functionalization of dendrimer proved important to a number of parameters including dendrimer-bacteria association, NO delivery efficiency, bacteria membrane disruption, migration within the biofilm, and toxicity to mammalian cells. Although enhanced bactericidal efficacy was observed for the hydrophobic chains (e.g., ED), toxicity to L929 mouse fibroblast cells was also noted at concentrations necessary to reduce bacterial viability by 5-logs (99.999% killing). The optimal PO to ED ratios for biofilm eradication with minimal toxicity against L929 mouse fibroblast cells were 7:3 and 5:5. The study presented herein demonstrated the importance of both dendrimer size and exterior properties in determining efficacy against established biofilms without compromising biocompatibility to mammalian cells.

| S-EPMC3815563 | biostudies-literature

Structurally Diverse Nitric Oxide-Releasing Poly(propylene Imine) Dendrimers.

Project description:Structurally diverse secondary amine-functionalized poly(propylene imine) (PPI) dendrimers capable of tunable nitric oxide (NO) release were synthesized in a straightforward, one-step manner using ring-opening or conjugate-addition reactions with propylene oxide (PO), styrene oxide (SO), acrylonitrile (ACN), poly(ethylene glycol) methyl ether acrylate (average Mn = 480) (PEG) or 1,2-epoxy-9-decene (ED). N-Diazeniumdiolate nitric oxide donors were formed on the resulting secondary amine-functionalized G2-G5 PPI dendrimers by reaction with NO gas in basic solution. The NO storage and release kinetics for the resulting dendritic scaffolds were diverse (0.9-3.8 μmol NO/mg totals and 0.3 to 4.9 h half lives), illustrating the importance of the exterior chemical modification (e.g., steric environments, hydrophobicity, etc.) on diazeniumdiolate stability/decomposition. Tunable NO release was demonstrated by combining two donor systems on the exterior of one macromolecular scaffold. Additionally, a mathematical model was developed that allows for the simulation of dual NO release kinetics using the NO release data from the two single NO donor systems. The approaches described herein extend the range and scope of NO-releasing macromolecular scaffolds by unlocking a series of materials for use as dopants in biomedical polymers or stand-alone therapeutics depending on the exterior modification.

| S-EPMC3204868 | biostudies-literature

Nitric oxide-releasing alginates as mucolytic agents.

Project description:The excessive production of thick, viscous mucus in severe respiratory diseases leads to obstruction of the airways and provides a suitable environment for the colonization of pathogenic bacteria. The effect of nitric oxide (NO)-releasing alginates with varying NO release kinetics on the viscoelastic properties of human bronchial epithelial (HBE) mucus was evaluated as a function of the NO-release kinetics using parallel plate rheology. Low molecular weight (~5 kDa) alginates with high NO flux (~4000 ppb/mg) and sustained release (half-life ~0.3 h) proved to be most effective in reducing both mucus elasticity and viscosity (≥60% reduction for both). The efficacy of the NO-releasing alginates was shown to be dose-dependent, with high concentrations of NO-releasing alginates (~80 mg•mL-1) resulting in greater reduction of the viscosity and elasticity of the mucus samples. Greater reduction in mucus rheology was also achieved with NO-releasing alginates at lower concentrations when compared to both NO-releasing chitosan, a similarly biocompatible cationic polymer, and N-acetyl cysteine (NAC), a conventional mucolytic agent.

| S-EPMC7164775 | biostudies-literature

Active Release of Nitric Oxide-Releasing Dendrimers from Electrospun Polyurethane Fibers.

Project description:The fabrication of electrospun composite polyurethane fibers capable of dual-action antibacterial dendrimer release is reported. Generation 4 (G4) poly(amidoamine) dendrimers were functionalized with octyl alkyl chain or quaternary ammonium (QA) moieties followed by modification of the resulting secondary amines with N-diazeniumdiolate nitric oxide (NO) donors to produce dual-action antibacterial dendrimers. Control and NO-releasing dendrimers were doped into polyurethane solutions prior to electrospinning of the polymer to yield well-defined dendrimer-doped composite polyurethane fibers. The fiber mats were semi-porous (≥30% porosity) and exhibited high water uptake (>100% relative to fiber mass). Dendrimer- and NO-release characteristics (rates and totals) were dependent on the dendrimer modification and polyurethane composition, with total dendrimer- and NO-release amounts ranging from 10 - 80 μg/mg and 0.027 - 0.072 μmol NO/mg, respectively. The antibacterial action of the fibers was evaluated against Gram-negative and Gram-positive bacterial strains. Nitric oxide-releasing fibers demonstrated broad-spectrum bactericidal action at short (2 h) and long (24 h) timescales.

| S-EPMC7164776 | biostudies-literature

Nitric oxide-releasing hyperbranched polyaminoglycosides for antibacterial therapy.

Project description:Hyperbranched polyaminoglycosides were prepared by the polymerization of kanamycin, gentamicin, and neomycin, and N,N'-methylenebis(acrylamide) via a one-pot reaction. The secondary amines at the linear units of the hyperbranched polymers were subsequently reacted with NO gas at high pressure under alkaline conditions to form N-diazeniumdiolate NO donors. The resulting NO-releasing hyperbranched polyaminoglycosides exhibited a wide range of NO payloads (~0.4-1.3 µmol mg-1) and release kinetics (half-lives ~70-180 min). The therapeutic utility of these materials was evaluated by examining their bactericidal activity against common dental pathogens and toxicity to human gingival fibroblast cells. The antibacterial efficacy of NO-releasing hyperbranched polyaminoglycosides was dependent on specific physiochemical properties, with greater degrees of branching and aminoglycoside terminal groups correlating to enhanced action. Nitric oxide-releasing hyperbranched polykanamycin and polyneomycin elicited the least cytotoxicity at bactericidal concentrations, indicating the greatest therapeutic index for future biomedical applications.

| S-EPMC7164780 | biostudies-literature

Antibacterial Activity of Nitric Oxide-Releasing Hyperbranched Polyamidoamines.

Project description:Hyperbranched polyamidoamines (h-PAMAM) were prepared using a one-pot reaction to have similar molecular weight to third generation PAMAM (G3-PAMAM) dendrimers, and then functionalized with N-diazeniumdiolate nitric oxide (NO) donors. A wide range of NO storage capacities (∼1-2.50 μmol mg-1) and NO-release kinetics (t1/2 ∼30-80 min) were achieved by changing the extent of propylene oxide (PO) modification. The therapeutic potential of these materials was evaluated by studying their antibacterial activities and toxicity against common dental pathogens and human gingival fibroblast cells, respectively. Our results indicate that the combination of NO release and PO modification is necessary to yield h-PAMAM materials with efficient bactericidal action without eliciting unwarranted cytotoxicity. Of importance, NO-releasing PO-modified h-PAMAM polymers exhibited comparable biological properties (i.e., antibacterial action and cytotoxicity) to defect-free G3-PAMAM dendrimers, but at a substantially lower synthetic burden.

| S-EPMC6773256 | biostudies-literature

Anionic amphiphilic dendrimers as antibacterial agents.

Project description:An anionic amphiphilic dendrimer is reported that possesses increased cytotoxicological potency against prokaryotic cells compared to eukaryotic cells. The half-maximal effective concentration (EC50) for the dendrimer against Bacillus subtilis, a Gram-positive bacterial strain, was measured to be 4.1 x 10(-5) M, while that against human umbilical vein endothelial cells (HUVEC) was more than 36x greater at a value of 1.5 x 10(-3) M. EC50 ratios for two commercial amphiphiles, sodium dodecyl sulfate (SDS) and Triton X-100, in addition to a similar synthesized dendritic structure were at most only 3.8x greater. Furthermore, the observed EC50 values appear to be correlated to the critical aggregation constant (CAC) in solution suggesting a mechanism of action for these anionic amphiphilic dendrimers related to their supramolecular structures.

| S-EPMC2673084 | biostudies-literature

Nitric Oxide-Releasing Alginates.

Project description:Low and high molecular weight alginate biopolymers were chemically modified to store and release potentially therapeutic levels of nitric oxide (NO). Carbodiimide chemistry was first used to modify carboxylic acid functional groups with a series of small molecule alkyl amines. The resulting secondary amines were subsequently converted to N-diazeniumdiolate NO donors via reaction with NO gas under basic conditions. NO donor-modified alginates stored between 0.4-0.6 μmol NO·mg-1. In aqueous solution, the NO-release kinetics were diverse (0.3-13 h half-lives), dependent on the precursor amine structure. The liberated NO showed bactericidal activity against Pseudomonas aeruginosa and Staphylococcus aureus with pathogen eradication efficiency dependent on both molecular weight and NO-release kinetics. The combination of lower molecular weight (∼5 kDa) alginates with moderate NO-release durations (half-life of ∼4 h) resulted in enhanced killing of both planktonic and biofilm-based bacteria. Toxicity against human respiratory epithelial (A549) cells proved negligible at NO-releasing alginate concentrations required to achieve a 5-log reduction in viability in the biofilm eradication assay.

| S-EPMC6759059 | biostudies-literature

Nitric Oxide-Releasing Cyclodextrins.

Project description:A series of secondary amine-modified cyclodextrin (CD) derivatives was synthesized with diverse exterior terminal groups (i.e., hydroxyl, methyl, methoxyl, and primary amine). Subsequent reaction with nitric oxide (NO) gas under alkaline conditions yielded N-diazeniumdiolate-modified CD derivatives. Adjustable NO payloads (0.6-2.4 μmol/mg) and release half-lives (0.7-4.2 h) were achieved by regulating both the amount of secondary amine precursors and the functional groups around the NO donors. The bactericidal action of these NO-releasing cyclodextrin derivatives was evaluated against Pseudomonas aeruginosa, a Gram-negative pathogen, with antibacterial activity proving dependent on both the NO payload and exterior modification. Materials containing a high density of NO donors or primary amines exhibited the greatest ability to eradicate P. aeruginosa. Of the materials prepared, only the primary amine-terminated heptasubstituted CD derivatives exhibited toxicity against mammalian L929 mouse fibroblast cells. The NO donor-modified CD was also capable of delivering promethazine, a hydrophobic drug, thus demonstrating potential as a dual-drug-releasing therapeutic.

| S-EPMC6790977 | biostudies-literature

Antibacterial action of nitric oxide-releasing hyperbranched polymers against ex vivo dental biofilms.

Project description:ObjectivesThis study investigates the antibiofilm action of nitric oxide (NO)-releasing hyperbranched polymers against ex vivo multispecies periodontal biofilms.MethodsThe antibiofilm efficacy of NO-releasing hyperbranched polymers was evaluated as a function of NO-release properties, polymer concentrations, and oxygen levels in the exposure media. 16s rRNA sequencing technique was employed to evaluate the impact of NO-releasing hyperbranched polymers on the microbial composition of the biofilms.ResultsThe addition of NO release significantly improved the antibiofilm action of the hyperbranched polymers, with NO-releasing hyperbranched polyamidoamines of largest NO payloads being more effective than hyperbranched polykanamycins. Furthermore, the NO-releasing hyperbranched polymers reduced the biofilm metabolic activity in a dose-dependent manner, killing biofilm-detached bacteria under both aerobic and anaerobic conditions, with greater antimicrobial efficacy observed under aerobic conditions.SignificanceThese results demonstrate for the first time the potential therapeutic utility of NO-releasing hyperbranched polymers for treating multispecies dental biofilms.

| S-EPMC7233373 | biostudies-literature

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