Host-Guest Antimicrobial Based on Conjugated Oligoelectrolyte and Cyclodextrin.

Area of Science:

• Medicinal Chemistry
• Supramolecular Chemistry
• Antimicrobial Resistance

Background:

• Antimicrobial resistance (AMR) is a growing global health crisis requiring novel therapeutic strategies.
• Resveratrol-derived conjugated oligoelectrolytes (COEs) offer potential antimicrobial properties but often face challenges with cytotoxicity.
• Amphiphilic antimicrobial agents frequently present a trade-off between efficacy and host cell toxicity.

Purpose of the Study:

• To develop a novel antimicrobial agent with improved drug-like properties and reduced cytotoxicity.
• To investigate the efficacy of a supramolecular host-guest complex for enhancing antimicrobial performance.
• To evaluate the potential of a resveratrol-derived COE complex against drug-resistant bacteria and in infection models.

Main Methods:

• Synthesis and characterization of a resveratrol-derived antimicrobial conjugated oligoelectrolyte (COE), DY6.
• Formation of a host-guest inclusion complex (DY6@SβCD) using sodium sulfobutyl ether β-cyclodextrin (SβCD).
• Assessment of cytotoxicity (IC50), antibacterial activity (MIC) against MRSA, and resistance development studies. In vitro and in vivo infection models were utilized.

Main Results:

• The DY6@SβCD complex significantly reduced cytotoxicity (IC50 > 128 µg mL-1) compared to DY6 (IC50 = 9.4 µg mL-1) while retaining potent activity against MRSA (MIC = 2 µg mL-1).
• Spectroscopic and calorimetric analyses confirmed stable host-guest complex formation, attributing enhanced biocompatibility to size compatibility and electrostatic interactions.
• DY6@SβCD demonstrated superior efficacy over vancomycin in reducing bacterial load and inflammation in MRSA-infected wound and corneal models, with no observed resistance development.

Conclusions:

• Supramolecular complexation of COEs with cyclodextrins is a viable strategy to mitigate cytotoxicity and enhance antimicrobial efficacy.
• The DY6@SβCD complex represents a promising therapeutic candidate for combating drug-resistant bacterial infections, including MRSA.
• This approach offers a pathway to overcome the inherent limitations of amphiphilic antimicrobials and address the challenge of antimicrobial resistance.