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De novo design and synthesis of ultra-short peptidomimetic antibiotics having dual antimicrobial and anti-inflammatory activities.


ABSTRACT:

Background

Much attention has been focused on the design and synthesis of potent, cationic antimicrobial peptides (AMPs) that possess both antimicrobial and anti-inflammatory activities. However, their development into therapeutic agents has been limited mainly due to their large size (12 to 50 residues in length) and poor protease stability.

Methodology/principal findings

In an attempt to overcome the issues described above, a set of ultra-short, His-derived antimicrobial peptides (HDAMPs) has been developed for the first time. Through systematic tuning of pendant hydrophobic alkyl tails at the N(?)- and N(?)-positions on His, and the positive charge of Arg, much higher prokaryotic selectivity was achieved, compared to human AMP LL-37. Additionally, the most potent HDAMPs showed promising dual antimicrobial and anti-inflammatory activities, as well as anti-methicillin-resistant Staphylococcus aureus (MRSA) activity and proteolytic resistance. Our results from transmission electron microscopy, membrane depolarization, confocal laser-scanning microscopy, and calcein-dye leakage experiments propose that HDAMP-1 kills microbial cells via dissipation of the membrane potential by forming pore/ion channels on bacterial cell membranes.

Conclusion/significance

The combination of the ultra-short size, high-prokaryotic selectivity, potent anti-MRSA activity, anti-inflammatory activity, and proteolytic resistance of the designed HDAMP-1, -3, -5, and -6 makes these molecules promising candidates for future antimicrobial therapeutics.

SUBMITTER: Murugan RN 

PROVIDER: S-EPMC3841161 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Publications

De novo design and synthesis of ultra-short peptidomimetic antibiotics having dual antimicrobial and anti-inflammatory activities.

Murugan Ravichandran N RN   Jacob Binu B   Ahn Mija M   Hwang Eunha E   Sohn Hoik H   Park Hyo-Nam HN   Lee Eunjung E   Seo Ji-Hyung JH   Cheong Chaejoon C   Nam Ky-Youb KY   Hyun Jae-Kyung JK   Jeong Ki-Woong KW   Kim Yangmee Y   Shin Song Yub SY   Bang Jeong Kyu JK  

PloS one 20131126 11


<h4>Background</h4>Much attention has been focused on the design and synthesis of potent, cationic antimicrobial peptides (AMPs) that possess both antimicrobial and anti-inflammatory activities. However, their development into therapeutic agents has been limited mainly due to their large size (12 to 50 residues in length) and poor protease stability.<h4>Methodology/principal findings</h4>In an attempt to overcome the issues described above, a set of ultra-short, His-derived antimicrobial peptide  ...[more]

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