Design, Synthesis and Antibacterial Studies of Novel Cationic Amphipathic Cyclic Undecapeptides and Their Linear Counterparts against Virulent Bacterial Strains

Hisham N Farrag,Tamaki Kato,Toshinari Maeda

doi:10.3390/scipharm89010010

Hisham N Farrag, Tamaki Kato + Show 1 more

Open Access

https://doi.org/10.3390/scipharm89010010

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Journal: Scientia Pharmaceutica	Publication Date: Feb 5, 2021
Citations: 4	License type: CC BY 4.0

Affiliation: Kyushu Institute of Technology

Abstract

Bacteria have acquired resistance against almost all antibiotics because of the misuse of antibacterial agents and long periods of treatment. Antimicrobial peptides (AMPs) are one of the most encouraging candidates to solve this problem, as they possess high prokaryotic selectivity, and affect the bacteria by a unique mode of action. Novel cyclic undecapeptides (QNRNFYFNRNQ and QNRNFHFNRNQ) and their linear counterparts were investigated for their antibacterial activity against virulent strains. The minimal inhibitory concentration (MIC) values showed that tyrosine and histidine AMPs have promising antibacterial activity against virulent bacteria. The MIC values against the P. aeruginosa PA14, E. coli O157:H7 CR3, S. aureus 209P, and B. subtilis ATCC 6633 bacterial strains were evaluated for the cyclic peptide containing tyrosine, and their values were 6.25, 12.5, 12.5, and 12.5 µM, respectively. Meanwhile, for the linear form, they were 9.3, 12.5, 12.5, and 12.5 µM, respectively. The cyclic-peptide–containing histidines’ MIC values were 6.25, 3.1, 6.25, and 3.1 µM, respectively. Meanwhile, for the linear form, they were 3.1, 3.1, 3.1, and 6.25 µM, respectively. The antibacterial activities of the new AMPs were compared with that of gentamicin sulfate, and showed relatively higher potencies. Time-inhibition studies demonstrated the rapid antibacterial effects of the novel AMPs, which were more likely to be concentration-dependent, rather than time-dependent. At double the MIC concentration, all of the tested peptides exhibited relatively stable antibacterial effects up to 24 h, especially the peptides containing tyrosine, which showed an improved antibacterial effect.

Highlights

The prevalence of nosocomial-acquired and community-developed diseases due to many virulent bacterial strains, such as Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Bacillus subtilis, have been growing recently [1]
The amphipathic character of a peptide indicates the presence of hydrophobic and cationic residues incorporated in the sequence
Tyrosine has an amphipathic character to assist in the penetration

Summary

Introduction

The prevalence of nosocomial-acquired and community-developed diseases due to many virulent bacterial strains, such as Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli, and Bacillus subtilis, have been growing recently [1]. The global emergent catastrophe of antibiotic resistance acquired by the virulent bacterial strains has underlined the necessity of the investigation of new substitutes for currently-existing antibiotics [2]. The amphipathic moieties included in AMPs initiate the interaction with the bacterial cell membranes. The amphipathic character of a peptide indicates the presence of hydrophobic and cationic residues incorporated in the sequence. These moieties start the interaction between the peptides and bacterial cell membranes through hydrophobic and electrostatic forces. These forces allow the peptide to penetrate the bacterial cell membranes, causing cell death [8]. The other mechanism of AMPs is the targeting of some vital cell components, such as DNA [9]

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Conclusion