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Broadening Activity of Polymyxin by Quaternary Ammonium Grafting.

ABSTRACT: Bacterial pathogens continue to impose a tremendous health burden across the globe. Here, we describe a novel series of polymyxin-based agents grafted with membrane-active quaternary ammonium warheads to combine two important classes of Gram-negative antimicrobial scaffolds. The goal was to deliver a targeted quaternary ammonium warhead onto the surface of bacterial pathogens using the outer membrane homing properties of polymyxin. The most potent agents resulted in new scaffolds that retained the ability to target Gram-negative bacteria and had limited toxicity toward mammalian cells. We showed, using a molecular dynamics approach, that the new agents retained their ability to engage in specific interactions with lipopolysaccharide molecules. Significantly, the combination of quaternary ammonium and polymyxin widens the activity to the pathogen Staphylococcus aureus. Our results serve as an example of how two membrane-active agents can be combined to produce a class of novel scaffolds with potent biological activity.

SUBMITTER: Ongwae GM

PROVIDER: S-EPMC7293573 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Improved antibacterial activity of hemp fibre by covalent grafting of quaternary ammonium groups.

Project description:In this study, a novel antibacterial hemp fibre grafted with quaternary ammonium groups (HF-GTA), were prepared by alkalization, oxidation, amination and quaternization multistage reactions. The chemical structure and micromorphology of the fibre were characterized by Fourier-transform infrared spectroscopy, scanning electron microscopy, X-ray photoelectron spectroscopy, thermogravimetric analysis and X-ray diffraction. The grafting and reaction mechanism proved to be successful, which indicated that the grafting reaction primarily occurred on the hydroxyl group of cellulose and hemicellulose in the hemp fibre, where it retained good fibrous morphology, thermal stability and hygroscopicity. HF-GTA exhibited the best antibacterial activity, where the antibacterial ratios against Escherichia coli and Staphylococcus aureus were 95.41% and 99.64%, respectively. Even after washing 30 times, the antibacterial activity was retained at 89.78% and 91.12%, indicating that HF-GTA was endowed with good washing resistance. The antibacterial activity was owing to the electrostatic reaction reducing the electrochemical potential on the cell membrane, leading to the release of cytoplasmic substances and the dissolution of cells. This study is significantly important for guaranteeing textile quality and preventing disease transmission.

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Mutagenic activity of quaternary ammonium salt derivatives of carbohydrates.

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Synthesis and Antibacterial Activity of Quaternary Ammonium 4-Deoxypyridoxine Derivatives.

Project description:A series of novel quaternary ammonium 4-deoxypyridoxine derivatives was synthesized. Two compounds demonstrated excellent activity against a panel of Gram-positive methicillin-resistant S. aureus strains with MICs in the range of 0.5-2??g/mL, exceeding the activity of miramistin. At the same time, both compounds were inactive against the Gram-negative E. coli and P. aeruginosa strains. Cytotoxicity studies on human skin fibroblasts and embryonic kidney cells demonstrated that the active compounds possessed similar toxicity with benzalkonium chloride but were slightly more toxic than miramistin. SOS-chromotest in S. typhimurium showed the lack of DNA-damage activity of both compounds; meanwhile, one compound showed some mutagenic potential in the Ames test. The obtained results make the described chemotype a promising starting point for the development of new antibacterial therapies.

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Synthesis, physiochemical property and antimicrobial activity of novel quaternary ammonium salts.

Project description:Twenty-four novel 5-phenyl-1,3,4-oxadiazole-2-thiol (POT) analogues, benzo[d]oxazole-2-thiol, benzo[d]thiazole-2-thiol and 5-methyl-1,3,4-thiadiazole-2-thiol-substituted N,N-bis(2-hydroxyethyl) quaternary ammonium salts (QAS) (5a-d, 6a-d, 7a-d, 10a-d, 13a-d, 16a-d) were prepared and characterised by FTIR, NMR and elemental analysis. Part of target compounds (5d, 6d, 7d, 10d, 13d, 16d) displayed potent antimicrobial effect against ten common pathogens (S. aureus, α-H-tococcus, β-H-tococcus, E. coli, P. aeruginosa, Proteus vulgaris, Canidia Albicans, Cytospora mandshurica, Physalospora piricola, Aspergillus niger) and had relatively low cytotoxity against two human cell lines (HaCat and LO2). TEM and SEM images of E. coli and S. aureus morphologies treated with 7d showed that the antibacterial mechanism might be the QAS fixing on cell wall surfaces and puncturing to result in the release of bacterial cytoplasm. This study provides new information of QAS, which could be used to design novel antimicrobial agents applied in clinic or agriculture.

| S-EPMC6010013 | biostudies-literature

Adaptation to quaternary ammonium compounds

Project description:Adaptation of Listeria monocytogenes EGD-e to quaternary ammonium compounds

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Project description:The synthesis and biological evaluation of a novel series of dimeric camphor derivatives are described. The resulting compounds were studied for their antiviral activity, cyto- and genotoxicity. Compounds 3a and 3d in which the quaternary nitrogen atoms are separated by the C5H10 and ?9H18 aliphatic chain, exhibited the highest efficiency as an agent inhibiting the reproduction of the influenza virus A(H1N1)pdm09. The cytotoxicity data of compounds 3 and 4 revealed their moderate activity against malignant cell lines; compound 3f had the highest activity for the CEM-13 cells. These results show close agreement with the data of independent studies on toxicity of these compounds, in particular that the toxicity of compounds strongly depends on spacer length.

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Novel Amino-Pyridine Functionalized Chitosan Quaternary Ammonium Derivatives: Design, Synthesis, and Antioxidant Activity.

Project description:Chemical modification of chitosan is increasingly studied for its potential of providing new applications of chitosan. Here, a group of novel chitosan quaternary ammonium derivatives containing pyridine or amino-pyridine were designed and successfully synthesized through chemical modification of chitosan. Pyridine and amino-pyridine were used as functional groups to improve the antifungal activity of chitosan derivatives. The chitosan derivatives' antioxidant activity against hydroxyl-radical and 1,1-Diphenyl-2-picrylhydrazyl (DPPH)-radical was tested in vitro. The results showed that chitosan derivatives had better water solubility and stronger antioxidant activity compared with chitosan in all assays. Especially, compounds 3C and 3E (with 3-amino pyridine and 2,3-diamino pyridine as substitute respectively) exhibited stronger hydroxyl-radical and DPPH-radical scavenging ability than other synthesized compounds. These data demonstrated that the synergistic effect of the amino group and pyridine would improve the antioxidant activity of chitosan derivatives, and the position of the amino group on pyridine could influence the antioxidant property of chitosan derivatives.

| S-EPMC6155944 | biostudies-literature

In Vitro Activity of Quaternary Ammonium Surfactants against Streptococcal, Chlamydial, and Gonococcal Infective Agents.

Project description:Quaternary ammonium compounds (QAC) are widely used, cheap, and chemically stable disinfectants and topical antiseptics with wide-spectrum antimicrobial activities. Within this group of compounds, we recently showed that there are significant differences between the pharmacodynamics of n-alkyl quaternary ammonium surfactants (QAS) with a short (C12) alkyl chain when in vitro toxicities toward bacterial and mammalian epithelial cells are compared. These differences result in an attractive therapeutic window that justifies studying short-chain QAS as prophylactics for sexually transmitted infections (STI) and perinatal vertically transmitted urogenital infections (UGI). We have evaluated the antimicrobial activities of short-chain (C12) n-alkyl QAS against several STI and UGI pathogens as well as against commensal Lactobacillus species. Inhibition of infection of HeLa cells by Neisseria gonorrhoeae and Chlamydia trachomatis was studied at concentrations that were not toxic to the HeLa cells. We show that the pathogenic bacteria are much more susceptible to QAS toxic effects than the commensal vaginal flora and that QAS significantly attenuate the infectivity of N. gonorrhoeae and C. trachomatis without affecting the viability of epithelial cells of the vaginal mucosa. N-Dodecylpyridinium bromide (C12PB) was found to be the most effective QAS. Our results strongly suggest that short-chain (C12) n-alkyl pyridinium bromides and structurally similar compounds are promising microbicide candidates for topical application in the prophylaxis of STI and perinatal vertical transmission of UGI.

| S-EPMC4879390 | biostudies-literature

Evaluation of virucidal activity of residual quaternary ammonium-treated surfaces on SARS-CoV-2.

Project description:BackgroundThe COVID-19 pandemic has had an unprecedented impact on global health and the world's economies. Proliferation of virulent and deadly SARS-CoV-2 variants require effective transmission mitigation strategies. Under reasonable environmental conditions, culturable and infectious SARS-CoV-2 can survive on contaminated fomites from hours to months. In the present study we evaluated a surface-anchored polymeric quaternary ammonium antimicrobial to help reduce fomite transmission of SARS-CoV-2 from contaminated surfaces.MethodsTwo studies were performed on antimicrobial pre-treated metal disks in March 2020 by two independent Biosafety Level III (BSL-3) equipped laboratories in April 2020. These facilities were in Belgium (the Rega Medical Research Institute) and Australia (the Peter Doherty Institute) and independently applied quantitative carrier-based methodologies using the authentic SARS-CoV-2 isolates (hCoV-19/Australia/VIC01/2020, hCoV-19/Belgium/GHB-03021/2020).ResultsResidual dry tests were independently conducted at both facilities and demonstrated sustained virion destruction (108.23 TCID50/carrier GHB-03021 isolate, and 103.66 TCID50/carrier VIC01 isolate) 1 hour (drying) + 10 minutes after inoculation. Reductions are further supported by degradation of RNA on antimicrobial-treated surfaces using qRT-PCR.ConclusionsUsing a polymeric quaternary ammonium antimicrobial (EPA/PMRA registered) the results independently support a sustained antiviral effect via SARS-CoV-2 virion destruction and viral RNA degradation. This indicates that silane-anchored quaternary ammonium compound (SiQAC-18) treated surfaces could play an important role in mitigating the communicability and fomite transmission of SARS-CoV-2.

| S-EPMC8553632 | biostudies-literature

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