Supramolecular Modulation of Antibacterial Activity of Ambroxol by Cucurbit[7]uril

Supramolecular encapsulation by cucurbit[7]uril (CB[7]) was recently demonstrated to provide a simple and efficient method for antibacterial activity regulation of antibiotics. In this work, CB[7] was shown to form binary host-guest complex with ambroxol hydrochloride (ABX), a clinical mucokinetic and expectorant drug, which was reported to exhibit certain antibacterial activity. ¹ H NMR titration and isothermal titration calorimetry experiment results suggested that the 4-hydroxyl cyclohexylamine group of ABX was included inside the CB[7] cavity, with a binding constant K_a of (6.69±0.11)×10⁵  M^-1 in phosphate buffered saline (PBS) solution, thermodynamically driven by both enthalpy change (ΔH=-12.2 kJ/mol) and entropy change (TΔS=21.1 kJ/mol). More importantly, ABX's inhibitory activity (MIC₅₀ ) against bacillary strains towards Pseudomonas aeruginosa and Escherichia coli strains was decreased from (5.11±0.31)×10^-6  M^-1 and (2.63±0.34)×10^-5  M^-1 to zero upon encapsulation by CB[7], and was subsequently recovered to almost its original activity when a competitive guest, amantadine hydrochloride, for disassembling CB[7]-ABX complex, was added, suggesting that the antibacterial activity of ABX could be readily "turned off/on" upon its complexation and decomplexation with CB[7].