LEGO-Lipophosphonoxin membrane activity is enhanced by presence of phosphatidylethanolamine but hindered by outer membrane

Résumé fourni par la source

Finding effective antibiotics against multi-resistant strains of bacteria has been a challenging race. Linker-Evolved-Group-Optimized-Lipophosphonoxins (LEGO-LPPOs) are small modular synthetic antibacterial compounds targeting the cytoplasmic membrane. Here we focused on understanding the reasons for the variable efficacy of selected LEGO-LPPOs (LEGO-1, LEGO-2, LEGO-3, and LEGO-4) differing in hydrophobic and linker module structure and length. LEGO-1-4 permeabilized cytoplasmic membrane of Staphylococcus aureus, Bacillus subtilis, Pseudomonas aeruginosa, and Escherichia coli, LEGO-1 with the longest linker module being the most effective. Gram-positive bacteria were more sensitive to LEGO-LPPO action compared to Gram-negatives, which was manifested as a delayed membrane permeabilization, higher minimal inhibitory concentration and lower amount of LEGO-LPPO bound to the cells. Outer membrane permeability measurements and time-kill assay showed that presence of the intact outer membrane brought about reduced susceptibility of Gram-negatives. Using liposome leakage and in silico simulations, we showed that membranes with major content of phosphatidylethanolamine were more prone to LEGO-LPPO permeabilization. The proposed mechanism stems from an electrostatic repulsion between highly positively charged LEGO-1 molecules and positively charged amino groups of phosphatidylethanolamine which destabilizes the membrane. Collectively, these data suggest that LEGO-LPPO membrane activity is enhanced by presence of phosphatidylethanolamine but hindered by presence of intact outer membrane.

Ce résumé expose les affirmations des auteurs. BNTIC ne l’interprète pas comme une validation indépendante des résultats.