Colistin does not self-assemble at physiologically relevant conditions

Abstract

Antimicrobial peptides (AMPs) have shown great potential against the ongoing rise of multi-drug resistant bacteria because of their high potency and effectiveness. Their clinical utility has, however, remained limited due to their severe side effects. As an exception, colistin (polymyxin E) is currently utilized as a last-resort option against severe gram-negative infections despite being cyto- and nephrotoxic. The ongoing efforts to reduce these side effects are hampered by the generally poor understanding of its mode of action and behavior in solution. A key question that has been debated is whether colistin self-assembles into micelles or remains as unimers in solution. Herein, we used synchrotron small-angle X-ray scattering (SAXS), small-angle neutron scattering (SANS), and molecular dynamics (MD) to show that colistin does not self-assemble in a wide range of physiologically relevant conditions. These contrasting findings, compared to previously reported results, provide important new insights into the behavior of colistin, aiding the understanding and potential improvement of this relevant AMP-based antibiotic.