Abstract
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.
Highlights
Novel drug delivery systems using nanotechnology are an alternative option for solving antimicrobial resistance
Several nanodrug delivery systems have been involved in the effective delivery of antimicrobials with great success, and currently, they are being been introduced into the market [9,10]
Data obtained from the mean hydrodynamic diameter (MHD), polydispersity index (PDI), ζ, drug encapsulation efficiency (DEE)%, and the in vitro drug release, were subjected to a one-way ANOVA and results were considered statistically significant at p-values < 0.05, with a 95% significance level
Summary
Novel drug delivery systems using nanotechnology are an alternative option for solving antimicrobial resistance. Loading of antibiotics into nanosized drug delivery systems offers higher drug pharmacokinetic profiles, enhanced antibacterial activity, and protects the drug from enzymatic destruction leading to fewer side effects [5,6]. These traits tend to address the limitations of conventional dosage forms, which have been used for treating infectious diseases since the introduction of antibiotics [7,8]. Quatsomes have been shown to offer protection against premature drug degradation; they have intracellular penetration [23]; and they can be a potential platform for Pharmaceutics 2020, 12, 1093 site-specific delivery of drugs Their described desirable qualities and their inherent antimicrobial activity make them suitable candidates for antibiotic delivery [13,23]. The succinct in vitro, in vivo, and in-silico evaluation of this novel pH-responsive quatsome is reported in this study
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