Avibactam-Cyclodextrin Inclusion Complexes: Computational and Thermodynamic Insights for Drug Delivery, Detection,...

Area of Science:

• Pharmaceutical Science
• Supramolecular Chemistry
• Environmental Science

Background:

• Multidrug resistance and antibiotic residues pose significant clinical and environmental challenges.
• Current methods for quantifying avibactam (AVI) lack the sensitivity for therapeutic drug monitoring and environmental surveillance.
• Cyclodextrins (CDs) offer potential for enhancing AVI stability, bioavailability, and detectability, and for scavenging residual AVI.

Purpose of the Study:

• To investigate the inclusion complexation of avibactam (AVI) with various cyclodextrins (CDs).
• To evaluate the binding affinities and stability of AVI-CD complexes using computational and experimental methods.
• To explore the potential of CD-AVI complexes for pharmaceutical formulations and decontamination strategies.

Main Methods:

• Molecular dynamics (MD) simulations to model AVI-CD interactions.
• Isothermal titration calorimetry (ITC) to experimentally determine binding thermodynamics.
• Density Functional Theory (DFT)-based non-covalent interaction (NCI) analysis to understand complex stability.

Main Results:

• Stable 1:1 inclusion complexes were formed between AVI and β-cyclodextrin (β-CD), 2,6-dimethyl-β-CD (DM-β-CD), and 2-hydroxypropyl-β-CD (HP-β-CD).
• Binding affinities (ΔG°) ranged from -3.11 to -3.64 kcal/mol for these β-CD derivatives, indicating favorable complexation.
• γ-cyclodextrin (γ-CD) showed weaker binding (ΔG° = -2.25 kcal/mol), and NCI analysis highlighted the importance of cooperative interactions and cavity complementarity.

Conclusions:

• β-CD derivatives are effective supramolecular hosts for avibactam (AVI).
• The observed CD-AVI affinities support the development of advanced analytical methods and drug delivery systems.
• These findings open new possibilities for environmental decontamination of residual AVI through molecular trapping.