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Polymyxin B and E (colistin), are a group of cationic charged cyclic antibiotic lipopeptides that are frequently used in the clinics to treat infections caused by the multidrug-resistant gram-negative bacteria. Since the interactions with the blood plasma drug-transport proteins may play a critical role in determining their pharmacological and pharmacokinetic profiles, we studied the binding properties of polymyxins to the human serum albumin (HSA) under simulated physiological conditions by the combination of biophysical approaches, such as isothermal titration calorimetry (ITC), fluorescence anisotropy, circular dichroism (CD) buttressed by computational studies. The HSA binding to the polymyxins was relatively strong (K_a ≈ 1.0 × 10⁷ M⁻¹). Molecular docking indicated that polymyxins bind to the cleft of HSA between domains I and III via the electrostatic interactions. This evidence was further confirmed by the …