Systematic comparison of activity and mechanism of antimicrobial peptides against nosocomial pathogens

The World Health Organisation has deemed several multi-drug resistant (MDR) nosocomial bacterial pathogens to be of significant threat to human health. A stark increase in morbidity, mortality and the burden to healthcare systems around the world can be attributed to the development of resistance in these bacteria. Accordingly, alternative antimicrobial agents have been sought as an attractive means to combat MDR pathogens, with one such example being antimicrobial peptides (AMPs). Given the reported activity of AMPs, including Pardaxin, MSI-78, dermaseptin-PC (DMPC) and Cecropin B, it is important to understand their activities and modes of action against bacteria for further AMP design. In this study, we compared these AMPs against a panel of nosocomial bacterial pathogens, followed by detailed mechanistic studies. It was found that Pardaxin (1–22) and MSI-78 (4–20) displayed the most pronounced antimicrobial activity against the tested bacteria. The mechanistic studies by membrane permeability and molecular dynamics simulation further confirmed the strong membrane interaction and structure of Pardaxin (1–22) and MSI-78 (4–20), which contributed to their potent activity. This study demonstrated a structure and activity guidance for further design of Pardaxin (1–22) and MSI-78 (4–20) as therapeutics against MDR pathogens. The different effects of DMPC (1–19) and Cecropin B (1–21) on membrane integrity and phospholipid membrane interactions provided critical information for the rational design of next-generation analogues with specificity against either Gram-negative or Gram-positive bacteria. • Detailed activity and mechanistic studies of AMPs, including Pardaxin, MSI-78, dermaseptin-PC (DMPC) and Cecropin B, against a panel of Gram-negative and Gram-positive bacteria. • The most active Pardaxin (1–22) and MSI-78 (4–20) displayed strong membrane activity towards Gram-negative and Gram-positive bacteria. • Different mechanisms of DMPC (1–19) and Cecropin B (1–21) against Gram-negative and Gram-positive bacteria will guide the rational design of new AMP analogues. • Molecular dynamics simulation further provided the details of their structure and activity relationship.