Counterion-induced antibiotic-based small-molecular micelles for methicillin-resistant Staphylococcus aureus...

A new counterion-induced small-molecule micelle (SM) with surface charge-switchable activities for methicillin-resistant Staphylococcus aureus (MRSA) infections is proposed. The amphiphilic molecule formed by zwitterionic compound and the antibiotic ciprofloxacin (CIP), via a "mild salifying reaction" of the amino and benzoic acid groups, can spontaneously assemble into counterion-induced SMs in water. Through vinyl groups designed on zwitterionic compound, the counterion-induced SMs could be readily cross-linked using mercapto-3, 6-dioxoheptane by click reaction, to create pH-sensitive cross-linked micelles (CSMs). Mercaptosuccinic acid was also decorated on the CSMs (DCSMs) by the same click reaction to afford charge-switchable activities, resulting in CSMs that were biocompatible with red blood cells and mammalian cells in normal tissues (pH 7.4), while having strong retention to negatively charged bacterial surfaces at infection sites, based on electrostatic interaction (pH 5.5). As a result, the DCSMs could penetrate deep into bacterial biofilms and then release drugs in response to the bacterial microenvironment, effectively killing the bacteria in the deeper biofilm. The new DCSMs have several advantages such as robust stability, a high drug loading content (∼ 30%), easy fabrication, and good structural control. Overall, the concept holds promise for the development of new products for clinical application. STATEMENT OF SIGNIFICANCE: We fabricated a new counterion-induced small-molecule micelle with surface charge-switchable activities (DCSMs) for methicillin-resistant Staphylococcus aureus (MRSA) infections. Compared with reported covalent systems, the DCSMs not only have improved stability, high drug loading content (∼ 30%), and good biosafety, but also have the environmental stimuli response, and antibacterial activity of the original drugs. As a result, the DCSMs exhibited enhanced antibacterial activities against MRSA both in vitro and in vivo. Overall, the concept holds promise for the development of new products for clinical application.