Scientists used computer simulations to see how the antimicrobial peptide LL‑37 (and three others) sticks to the inner membrane of the drug‑resistant bug Acinetobacter baumannii. They found that the way these peptides affect the membrane changes a lot depending on whether the bacteria’s membrane contains more polyunsaturated fats, and on the peptide’s size and charge. This shows that bacterial membrane makeup can influence how well such peptides work, but the study doesn’t give any direct tips for human use.

The Gram-negative pathogen <i>Acinetobacter baumannii</i> is a primary contributor to nosocomial multi-drug-resistant (MDR) infections. To combat the rise of MDR infections, novel features of <i>A. baumannii</i> need to be considered for the development of new treatment options. One such feature is the preferential scavenging of exogenous lipids, including host-derived polyunsaturated fatty acids (PUFAs), for membrane phospholipid synthesis. These alterations in membrane composition impact both the lipid chemistry and the membrane biophysical properties. In this work we examine how antimicrobial peptides (AMPs) interact with the inner membranes of <i>A. baumannii</i> in the presence and absence of polyunsaturated phospholipids. Using coarse-grained molecular dynamics simulations of complex <i>A. baumannii</i> inner membrane models derived from lipidomes of bacteria grown in the presence and absence of PUFAs, we examine the impact of the adsorption of four prototypical AMPs (CAMEL, LL-37, pexiganan, and magainin-2) on the membrane biophysical properties. Our simulations reveal that the impact of AMP adsorption on the membrane biophysical properties was dependent on both the membrane composition and the specific AMP involved. Both lipid headgroup charge and tail unsaturation played important roles in driving the interactions that occurred both within the membrane and between the membrane and AMPs. The changes to the membrane biophysical properties also showed a complex relationship with the AMP's physical properties, such as AMP charge, chain length, and charge-to-mass ratio. Cumulatively, this work highlights the importance of studying AMPs using a complex membrane environment and provides insights into the mechanistic action of AMPs in polyunsaturated lipid-rich bacterial membranes.