Analysis of the Destabilization of Bacterial Membranes by Quaternary Ammonium Compounds: A Combined Experimental and Computational Study

Alkhalifa, Saleh; Jennings, Megan C.; Granata, Daniele; Klein, Michael L.; Wuest, William M.; Minbiole, Kevin P. C.; Carnevale, Vincenzo

doi:10.1002/cbic.201900698

Cited by 62 publications

(52 citation statements)

References 33 publications

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“…The interaction of the VCM-loaded StBAclm-Qt1 quatsomes with the MRSA could be due to the antibacterial activity of quaternary bicephalic surfactant, which resulted in the effective delivery of the VCM, leading to bacteria membrane disruption. Quaternary ammonium compounds have long been assumed to disrupt bacterial membranes through electrostatic attraction, followed by intercalation and subsequent disruption [ 95 ]. The investigation into how the quatsomes were functionalized revealed that Gram-positive bacteria (MRSA) appear to be affected by the antimicrobial properties of the quatsomes.…”

Section: Resultsmentioning

confidence: 99%

Formulation of pH-Responsive Quatsomes from Quaternary Bicephalic Surfactants and Cholesterol for Enhanced Delivery of Vancomycin against Methicillin Resistant Staphylococcus aureus

et al. 2020

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Globally, human beings continue to be at high risk of infectious diseases caused by methicillin-resistant Staphylococcus aureus (MRSA); and current treatments are being depleted due to antimicrobial resistance. Therefore, the synthesis and formulation of novel materials is essential for combating antimicrobial resistance. The study aimed to synthesize a quaternary bicephalic surfactant (StBAclm) and thereof to formulate pH-responsive vancomycin (VCM)-loaded quatsomes to enhance the activity of the antibiotic against MRSA. The surfactant structure was confirmed using 1H, 13C nuclear magnetic resonance (NMR), Fourier-transform infrared spectroscopy (FT-IR), and high-resolution mass spectrometry (HRMS). The quatsomes were prepared using a sonication/dispersion method and were characterized using various in vitro, in vivo, and in silico techniques. The in vitro cell biocompatibility studies of the surfactant and pH-responsive vancomycin-loaded quatsomes (VCM-StBAclm-Qt1) revealed that they are biosafe. The prepared quatsomes had a mean hydrodynamic diameter (MHD), polydispersity index (PDI), and drug encapsulation efficiency (DEE) of 122.9 ± 3.78 nm, 0.169 ± 0.02 mV, and 52.22 ± 8.4%, respectively, with surface charge switching from negative to positive at pH 7.4 and pH 6.0, respectively. High-resolution transmission electron microscopy (HR-TEM) characterization of the quatsomes showed spherical vesicles with MHD similar to the one obtained from the zeta-sizer. The in vitro drug release of VCM from the quatsomes was faster at pH 6.0 compared to pH 7.4. The minimum inhibitory concentration (MIC) of the drug loaded quatsomes against MRSA was 32-fold and 8-fold lower at pH 6.0 and pH 7.4, respectively, compared to bare VCM, demonstrating the pH-responsiveness of the quatsomes and the enhanced activity of VCM at acidic pH. The drug-loaded quatsomes demonstrated higher electrical conductivity and a decrease in protein and deoxyribonucleic acid (DNA) concentrations as compared to the bare drug. This confirmed greater MRSA membrane damage, compared to treatment with bare VCM. The flow cytometry study showed that the drug-loaded quatsomes had a similar bactericidal killing effect on MRSA despite a lower (8-fold) VCM concentration when compared to the bare VCM. Fluorescence microscopy revealed the ability of the drug-loaded quatsomes to eradicate MRSA biofilms. The in vivo studies in a skin infection mice model showed that groups treated with VCM-loaded quatsomes had a 13-fold decrease in MRSA CFUs when compared to the bare VCM treated groups. This study confirmed the potential of pH-responsive VCM-StBAclm quatsomes as an effective delivery system for targeted delivery and for enhancing the activity of antibiotics.

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Section: Resultsmentioning

confidence: 99%

Formulation of pH-Responsive Quatsomes from Quaternary Bicephalic Surfactants and Cholesterol for Enhanced Delivery of Vancomycin against Methicillin Resistant Staphylococcus aureus

et al. 2020

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“…They are bactericidal across a range of microorganisms, including fungi, bacteria, parasites and lipophilic viruses [ 10 ]. Due to their aliphatic nature, QACs act as cationic surfactants; therefore, they destabilize the cell membranes and enzymes of target microorganisms, resulting in cell lysis [ 11 , 12 , 13 ]. Examples include benzalkonium chloride and cetylpyridinum chloride, both of which can target Gram-negative and Gram-positive bacteria such as Escherichia coli and Staphylococcus aureus , respectively [ 14 ].…”

Section: Quaternary Ammonium Compounds (Qacs)mentioning

confidence: 99%

Biocide Use in the Antimicrobial Era: A Review

2021

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Biocides are widely used in healthcare and industry to control infections and microbial contamination. Ineffectual disinfection of surfaces and inappropriate use of biocides can result in the survival of microorganisms such as bacteria and viruses on inanimate surfaces, often contributing to the transmission of infectious agents. Biocidal disinfectants employ varying modes of action to kill microorganisms, ranging from oxidization to solubilizing lipids. This review considers the main biocides used within healthcare and industry environments and highlights their modes of action, efficacy and relevance to disinfection of pathogenic bacteria. This information is vital for rational use and development of biocides in an era where microorganisms are becoming resistant to chemical antimicrobial agents.

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“…Further, all of the tested N‐alkylpyridinium compounds displayed remarkable selectivity for Gram‐positive bacteria surpassing that of CPC and BAC. This result is normally indicative of a mechanism of action involving disruption of the plasma membrane, considering the low hemolytic activity seen in Table 1 it is likely that these compounds are permeabilizing the membrane and not lysing akin to recent discoveries in our lab [8] . Compound 8 shows an added level of selectivity, showing an 8 fold preference to inhibit the growth of S. mutans relative to S. aureus .…”

Section: Figurementioning

confidence: 76%

“…Many QACs can attribute their antimicrobial activity to their amphipathic nature, allowing for permeabilization and eventual lysis of plasma membranes [8] . This often results in selective inhibition of Gram‐positive bacteria, as these species lack the additional outer membrane seen in Gram‐negative bacteria.…”

Section: Figurementioning

confidence: 99%

Tricepyridinium‐inspired QACs yield potent antimicrobials and provide insight into QAC resistance

2020

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Quaternary ammonium compounds (QACs) comprise a large class of surfactants, consumer products, and disinfectants. The recently‐isolated QAC natural product tricepyridinium bromide displays potent inhibitory activity against S. aureus but due to its unique structure, its mechanism of action remains unclear. A concise synthetic route to access tricepyridinium analogs was thus designed and four N‐alkyl compounds were generated in addition to the natural product. Biological analysis of these compounds revealed that they display remarkable selectivity towards clinically‐relevant Gram‐positive bacteria exceeding that of commercially‐available QACs such as cetylpyridinium chloride (CPC) and benzalkonium chloride (BAC) while having little to no hemolytic activity. Molecular modeling studies revealed that tricepyridinium and shorter‐chain N‐alkyl analogs may preferentially bind to the QacR transcription factor leading to potential activation of the QAC resistance pathway found in MRSA; however, our newly synthesized analogs are able to overcome this liability.

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Analysis of the Destabilization of Bacterial Membranes by Quaternary Ammonium Compounds: A Combined Experimental and Computational Study

Abstract: In special dedication to Dr.Faina Ryvkin for her many years of servicet os tudents at Emmanuel College, Boston.

Cited by 62 publications

References 33 publications

Formulation of pH-Responsive Quatsomes from Quaternary Bicephalic Surfactants and Cholesterol for Enhanced Delivery of Vancomycin against Methicillin Resistant Staphylococcus aureus

Formulation of pH-Responsive Quatsomes from Quaternary Bicephalic Surfactants and Cholesterol for Enhanced Delivery of Vancomycin against Methicillin Resistant Staphylococcus aureus

Biocide Use in the Antimicrobial Era: A Review

Tricepyridinium‐inspired QACs yield potent antimicrobials and provide insight into QAC resistance

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