Polymyxin Stereochemistry and Its Role in Antibacterial Activity and Outer Membrane Disruption

With increasing rates of resistance toward commonly used antibiotics, especially among Gram-negative bacteria, there is renewed interested in polymyxins. Polymyxins are lipopeptide antibiotics with potent anti-Gram-negative activity and are generally believed to target lipid A, the lipopolysaccharide (LPS) anchor found in the outer membrane of Gram-negative bacteria. To characterize the stereochemical aspects of their mechanism(s) of action, we synthesized the full enantiomers of polymyxin B and the polymyxin B nonapeptide (PMBN). Both compounds were compared with the natural compounds in biological and biophysical assays, revealing strongly reduced antibacterial activity for the enantiomeric species. The enantiomeric compounds also exhibit reduced LPS binding, lower outer membrane (OM) permeabilization, and loss of synergetic potential. These findings provide new insights into the stereochemical requirements underlying the mechanisms of action of polymyxin B and PMBN.

Automated summary

With increasing antibiotic resistance, there is renewed interest in polymyxins, a type of lipopeptide antibiotics with potent anti-Gram-negative activity. This study synthesized the full enantiomers of polymyxin B and the polymyxin B nonapeptide (PMBN) to investigate their mechanism of action. The enantiomeric species showed reduced antibacterial activity, lower LPS binding, lower outer membrane permeabilization, and loss of synergetic potential, providing new insights into the stereochemical requirements of polymyxin B and PMBN.