In Vitro and In Vivo Antimicrobial Activity of Antibiotic-Conjugated Carriers with Rapid pH-Responsive Release Kinetics.

Two representative antibiotics, cephradine (CP) and moxifloxacin (MX), are covalently conjugated with a β-cyclodextrin (β-CD)-based carrier via pH-responsive 1-methyl-2-(2'-carboxyethyl) maleic acid amide (MCM) linkers with excellent conjugation efficiency via simple mixing. At pH 5.5, 90% and 80% of the CP and MX, respectively, are released from the carriers within 30 min, in contrast with the much-delayed release profile at pH 7.4. The in vitro inhibitory effect of β-CD-MCM-CP on the growth of Staphylococcus aureus is significantly lower than that of free CP at pH 7.4, but it reaches the level of free CP at pH 5.5. Moreover, S. aureus develops significant CP resistance after pretreatment with free CP, whereas the initial CP sensitivity is maintained after pretreatment with β-CD-MCM-CP at pH 7.4. However, β-CD-MCM-MX exhibits no such pH-responsive activity against Bacteroides fragilis, probably due to the insufficient stability of the MX conjugation at pH 7.4. In nondiabetic and diabetic mouse models, β-CD-MCM-CP significantly reduces the subcutaneous abscess scores and the bacterial counts in the abscess, although this represents only a marginal improvement in antimicrobial activity compared to free CP.