Multidrug-resistant bacterial infections have become a major public health concern. Thus, there is an urgent need to develop new classes of antibiotics with a different mechanism of action against resistant bacteria. Antimicrobial peptides (AMPs) have been reported as potential therapeutic agents against antibiotic-resistant bacteria due to their mode of action as regulators of the immune system and inhibition of bacterial cell growth. We have previously reported that amphiphilic cyclic peptide [R4W4] has antibacterial activity with a minimum inhibitory concentration (MIC) value of 2.97 μg/ml against Methicillin-resistant Staphylococcus aureus (MRSA). The objective of this work was to design, synthesize, and evaluate linear and cyclic peptide analogs R4X4 by using appropriate hydrophobic residues in combination with positively charged arginine residues to establish the structure-activity relationship. R4X4 sequence was selected as the scaffold based on the preliminary antibacterial data on the [R4W4]. The selected hydrophobic amino acids in the peptides sequence were tryptophan, leucine, isoleucine, alanine, phenylalanine, and tyrosine. Fmoc/tBu solid phase chemistry was used for the assembling the peptide on the resin. After acidic cleavage, the cyclization was used to generate six cyclic peptides. The corresponding six linear peptides (R4X4) were synthesized for the comparative studies with cyclic peptide [R4X4] to determine the key residues in the peptide sequence required for antibacterial activity. All the peptides were purified by reverse-phase HPLC and characterized by high-resolution MALDI mass spectrometry. The toxicity evaluation of the linear and cyclic peptide against normal kidney cells showed no significant toxicity at a concentration of 50 uM. Antibacterial activities for synthesized peptides will be evaluated against multidrug-resistant bacteria such as E. coli and MRSA. The outcome of this project expands our understanding of optimal structural requirements for the potent antibacterial activity against MRSA and other bacterial strains.

Synthesis of amphiphilic linear and cyclic peptides containing arginine and hydrophobic residues as potent antibacterial agents

251st National Meeting (2016)

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