Designed positively charged cyclodextrin hosts with enhanced binding of penicillins as carriers for the delivery of antibiotics: The case of oxacillin

In an effort to identify the optimal cyclodextrin (CD) host for delivery of penicillins to mammalian cells that will also offer protection against beta-lactamase-induced hydrolysis, nuclear magnetic resonance (NMR) spectroscopy and isothermal titration calorimetry (ITC) have been employed to study the inclusion complexes formed in aqueous solution between designed CD derivatives and two aminopenicillins, ampicillin and amoxicillin, and two antistaphylococcal penicillins, methicillin and oxacillin. Anionic and cationic thioether-substituted-beta- and - gamma CD derivatives were thus synthesized and compared with the neutral, parent CDs for complexation with the penicillins. The synthesized derivatives were shown to present similar to 20% elongated cavity space in solution. Moreover, the cationic ones are >98% protonated at physiological pH. The most efficient host was the positively charged octakis[6-(2-aminoethylthio)- 6-deoxy]-gamma-CD (gamma Cys) that formed the strongest complex with oxacillin (K-b similar to 1700 M - 1) in an enthalpically and entropically favorable process (Delta H-b = - 10.5 kJ/mol, T Delta S-b = 8.0 kJ/mol). In vitro biological tests demonstrated that gCys reduces 2.3-fold the rate of hydrolysis of oxacillin in the presence of oxa-1 beta-lactamase while displaying cell crossing capability and efficient internalization into macrophages as well as a sufficiently safe cytotoxicity profile. Overall, gamma Cys could be considered as a promising vehicle for protection and delivery of oxacillin. (C) 2017 Elsevier B.V. All rights reserved.