Design, synthesis and mode of action of short biphenyl and anthranilamide cationic peptidomimetics

Abstract

Antimicrobial resistance is a major worldwide threat to public health and there is an urgent need for the development of novel antibacterial agents. This research project focused on the development of short cationic peptidomimetics that employ 3'-amino-[1, 1 '-biphenyl)-3-carboxylic acid and anthranilic acidbackbones segregated by hydrophobic and cationic groups. The biphenyl peptidomimetic compounds showed that simple diaminoethanes and their respective guanidine cationic groups were sufficient to mimic lysine and arginine amino acids of natural antimicrobial peptides. The biphenyl backbone was important for antibacterial activity and tryptophan was important for bacterial cell membrane permeability. The most active compound showed good minimum inhibitory concentrations (MIC) against S. aureus (15.6 μM) and E.coli (7.8 μM) but was inactive against P. aeruginosa strain PA01. Based on these results, anthranilamide derivatives with tryptophan and simple amine cationic groups were developed. The anthranilamide peptidomimetic compounds showed that the guanidine group was important for good antibacterial activity against S. aureus (3.9 μM), E.coli (15.6 μM), and these compounds had low cytotoxicity (>100 μM). Active compounds disrupted 75% of established S. aureus biofilms. Biphenyl could be used as an alternative to naphthoyl groups to give hydrophobic groups to the mimetics. Increasing the net charge by adding lysine decreased antibacterial activity compared to compounds containing simple amine groups but improved the compound's cytotoxicity.Various alkyl-substituted guanidine compounds were investigated. Increasing the lipophilicity (adding alkyl groups) at the guanidine residues decreased antibacterial activity. Increasing the cationicity increased antibacterial activity against P. aeruginosa. The most active compound showed broad-spectrumantibacterial activity of against S. aureus (2.0 μM), E.coli (7.8 μM), and P. aeruginosa (32.0 μM). The active compounds at 4.0-8.0 μM showed significant disruption (55-77%) of preformed S. aureus biofilms and one compound at 15.6 μM disrupted 45% of E.coli biofilms. Peptidomimetics are promising future antibiotics. These compounds can potentially circumvent current antimicrobial resistance that is generated when bacteria produce biofilms