The Origin of Antimicrobial Resistance and Fluidity Dependent Membrane Structural Transformation by Antimicrobial Peptide Protegrin-1

In order to kill bacteria, antimicrobial peptides (AMPs) need to intercalate into bacterial membranes, diffuse laterally, and forms pore. Membrane fluidity is thus a critical aspect in AMP-mediated killing. We studied the proposition in this work by systematically examining the effect of membrane fluidity on the disruption of lipid bilayer by AMP protegrin-1 (PG-1). In a fluid supported bilayer patch, PG-1 induces edge instability, then pore-like surface defects at low concentration, and finally wormlike micelles at higher concentrations. We show that the lipid in fluid phase is more susceptible to the formation of pore and wormlike micelle. The progress of destabilizing gel phase to structural transformations occurred along with crack formation and disordering of the gel phase into fluid phase. In addition, we found that, even with the same phase, longer chain length contributed to the PG-1 resistance. Lastly, we provide clear evidence that altering the fluidity of the bilayer can give rise to AMP resistance. These results agree with other studies in which membrane lysis by antimicrobial peptide occurs preferentially at temperatures above the liquid crystal-gel phase transition of the lipid bilayers. Our works provide possible explanation to one of the physical mechanisms of AMP resistance developed by bacteria in the nature.