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

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.

Gemini and Bicephalous Surfactants: A Review on Their Synthesis, Micelle Formation, and Uses

“…On the other hand, Hanssan et al proposed a three-step synthesis to obtain a quaternary bicephalous cationic surfactant through the Michael reaction, using a different precursor to the previously reported synthetic methods [151]. They used trihexylamine with tert-butylacrylate only using methanol (MeOH) (step 1).…”

“…They used trihexylamine with tert-butylacrylate only using methanol (MeOH) (step 1). The product obtained reacts with triisopropylsilane (TIPs) and trifluoroacetic acid (TFA) (step 2), and finally the On the other hand, Hanssan et al proposed a three-step synthesis to obtain a quaternary bicephalous cationic surfactant through the Michael reaction, using a different precursor to the previously reported synthetic methods [151]. They used trihexylamine with tert-butylacrylate only using methanol (MeOH) (step 1).…”

“…The toxic and hemolytic results demonstrated its biosafety and antimicrobial effect, which was improved up to eight times compared to a formulation without the use of the quaternary cationic bicephalic surfactant. In addition, sustained drug release was achieved by an intelligent system sensitive to pH 7.4 [151].…”

Self-targeting of zwitterion-based platforms for nano-antimicrobials and nanocarriers

“…The combination of current antibiotics with various self-targeting platforms generating ROS inside an infectious biofilm or delivering antibiotics into the depth of a biofilm, has provided a new means to kill multi-drug resistant bacteria. 55,56 Therewith, a direly-needed pathway for future research has been lined out for the control of antimicrobial-resistant infections through the use of self-targeting nano-antimicrobials and nanocarriers, very similar to the pathway applied for the control of malignant tumors. 2,57 The next challenge with respect to bacterial infection control will be the translation of self-targeting nanoantimicrobials and antimicrobial nanocarriers from successful animal experiments to human clinical trials and application.…”

Photodynamic Antimicrobial Chemotherapy: Advancements in Porphyrin-Based Photosensitize Development

“…However, when the porphyrin was loaded to a cationic liposome, the phototoxicity effects against the bacteria increased remarkably. The increased effect upon loading the synthesized porphyrin in the cationic delivery system was attributed to the increased positive charge density ( Hassan et al, 2020 ) that destroyed the bacterial wall, thereby enhancing the permeability of the photosensitizer. A similar study was reported by Bombelli and co-workers ( Bombelli et al, 2008 ).…”