Design and synthesis of short amphiphilic cationic peptidomimetics based on biphenyl backbone as antibacterial agents

• Published in: European journal of medicinal chemistry 2018-01, Vol.143, p.1702-1722
• Main Authors: Kuppusamy, Rajesh, Yasir, Muhammad, Berry, Thomas, Cranfield, Charles G., Nizalapur, Shashidhar, Yee, Eugene, Kimyon, Onder, Taunk, Aditi, Ho, Kitty K.K., Cornell, Bruce, Manefield, Mike, Willcox, Mark, Black, David StC, Kumar, Naresh
• Format: Article
• Language: English
• Subjects: Antibiofilm activity; Antimicrobial peptide; Membrane disruption; Peptidomimetics
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2017.10.066

Antimicrobial peptides (AMPs) and their synthetic mimics have received recent interest as new alternatives to traditional antibiotics in attempts to overcome the rise of antibiotic resistance in many microbes. AMPs are part of the natural defenses of most living organisms and they also have a unique mechanism of action against bacteria. Herein, a new series of short amphiphilic cationic peptidomimetics were synthesized by incorporating the 3′-amino-[1,1′-biphenyl]-3-carboxylic acid backbone to mimic the essential properties of natural AMPs. By altering hydrophobicity and charge, we identified the most potent analogue 25g that was active against both Gram-positive Staphylococcus aureus (MIC = 15.6 μM) and Gram-negative Escherichia coli (MIC = 7.8 μM) bacteria. Cytoplasmic permeability assay results revealed that 25g acts primarily by depolarization of lipids in cytoplasmic membranes. The active compounds were also investigated for their cytotoxicity to human cells, lysis of lipid bilayers using tethered bilayer lipid membranes (tBLMs) and their activity against established biofilms of S. aureus and E. coli. This paper describes the importance of the biphenyl group as a backbone segregating with hydrophobic groups on one side and the cationic groups on the opposite side of the molecular structure to mimic the essential properties of natural antimicrobial peptides (AMPs). [Display omitted] •New biphenyl based amphiphiliccationic peptidomimetics were synthesized and evaluated for their antibacterialactivities.•Short cationic peptidomimetics displayed importance of biphenyl backbone for antibacterial activity.•Their hydrophobicity and net charge were important for the potent antibacterial activity.•Their mode of action explained by model tBLMs and membrane depolarization.•Biphenyl based peptidomimetics displayed moderate anti-biofilm activity.