Membrane Modification and Adaptation of Metabolism by Acinetobacter baumannii Prompts Resistance to Antimicrobial Activity of Outer Membrane Perturbing Peptide L8

Multidrug resistant (MDR) Acinetobacter baumannii has emerged as one of the most concerning nosocomial pathogens worldwide. One approach to target MDR A. baumannii is treatment with synergistic combinations of outer membrane-permeabilizing antimicrobial peptides (AMP) and antibiotics that otherwise only act against Gram-positive bacteria. Resistance against AMPs is rarely observed, especially when administered in combination with other drugs. Recently, we described the synergistic antimicrobial activity of AMPs L8 and L8S1 with rifampicin against a clinical isolate of A. baumannii. In the current work we explore the mechanisms of action of these peptides. We demonstrate that L8 and L8S1 perturb the cell envelope of A. baumannii. Moreover, we show that resistance against peptide L8 could be acquired in vitro either by increasing the amount of PE lipid on the surface or by increasing biofilm formation. Interestingly, the resistance to the antimicrobial activity of the peptides did not affect membrane perturbation or synergistic activity of the peptides with rifampicin, suggesting a dual mechanism of action for these peptides.