Design, Synthesis, and Evaluation of Amphiphilic Cyclic and Linear Peptides Composed of Hydrophobic and Positively-Charged Amino Acids as Antibacterial Agents

摘要

Antimicrobial peptides (AMPs) contain amphipathic structures and are derived fromnatural resources. AMPs have been found to be effective in treating the infections causedby antibiotic-resistant bacteria (ARB), and thus, are potential lead compounds against ARB.AMPs’ physicochemical properties, such as cationic nature, amphiphilicity, and their size, willprovide the opportunity to interact with membrane bilayers leading to damage and death ofmicroorganisms. Herein, AMP analogs of [R4W4] were designed and synthesized by changing thehydrophobicity and cationic nature of the lead compound with other amino acids to provide insightsinto a structure-activity relationship against selected model Gram-negative and Gram-positivepathogens. Clinical resistant strains of methicillin-resistant Staphylococcus aureus (MRSA) andEscherichia coli (E. coli) were used in the studies. Our results provided information about the structuralrequirements for optimal activity of the [R4W4] template. When tryptophan was replaced withother hydrophobic amino acids, such as phenylalanine, tyrosine, alanine, leucine, and isoleucine,the antibacterial activities were significantly reduced with MIC values of >128 μg/mL. Furthermore,a change in stereochemistry caused by D-arginine, and use of N-methyltryptophan, resulted in atwo-fold reduction of antibacterial activity. It was found that the presence of tryptophan is criticalfor antibacterial activity, and could not be substituted with other hydrophobic residues. The studyalso confirmed that cyclic peptides generally showed higher antibacterial activities when comparedwith the corresponding linear counterparts. Furthermore, by changing tryptophan numbers in thecompound while maintaining a constant number of arginine, we determined the optimal numberof tryptophan residues to be four, as shown when the number of tryptophan residues increased,a decrease in activity was observed.