An Amphipathic Undecapeptide with All d -Amino Acids Shows Promising Activity against Colistin-Resistant Strains of Acinetobacter baumannii and a Dual Mode of Action

Multiple strains ofAcinetobacter baumannii have developed multidrug resistance (MDR), leaving colistin as the only effective treatment. The cecropin-α–melittin hybrid BP100 (KKLFKKILKYL-NH2 ) and its analogs have previously shown activity against a wide array of plant and human pathogens. In this study, we investigated thein vitro antibacterial activities of 18 BP100 analogs (four known and 14 new) against the MDRA. baumannii strain ATCC BAA-1605, as well as against a number of other clinically relevant human pathogens. Selected peptides were further evaluated against strains ofA. baumannii that acquired resistance to colistin due to mutations of thelpxC ,lpxD ,pmrA , andpmrB genes. The novel analogue BP214 showed antimicrobial activity at 1 to 2 μM and a hemolytic 50% effective concentration (EC50 ) of >150 μM. The lower activity of its enantiomer suggests a dual, specific and nonspecific mode of action. Interestingly, colistin behaved antagonistically to BP214 whenpmrAB andlpxC mutants were challenged.