Self-assembly behaviour of colistin and its prodrug colistin methanesulfonate: implications for solution stability and solubilization

摘要

Colistin is an amphiphilic antibiotic that has re-emerged into clinical use due to the increasing prevalence of difficult-to-treat Gram-negative infections. The existence of self-assembling colloids in solutions of colistin and its derivative prodrug, colistin methanesulfonate (CMS) was investigated. Colistin and CMS reduced the air-water interfacial tension, and dynamic light scattering (DLS) studies showed the existence of 2.07 ± 0.3 nm aggregates above 1.5 mM for colistin, and of 1.98 ± 0.36 nm aggregates for CMS above 3.5 mM (mean ± SD). Above the respective critical micelle concentrations (CMC) the solubility of azithromycin, a hydrophobic antibiotic, increased approximately linearly with increasing surfactant concentration (5:1 mol ratio colistin:azithromycin), suggestive of hydrophobic domains within the micellar cores. Rapid conversion of CMS to colistin occurred below the CMC (60 % over 48 hr), while conversion above the CMC was less than 1 %. The formation of colistin and CMS micelles demonstrated in this study is the proposed mechanism for solubilization of azithromycin and the concentration-dependent stability of CMS.