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Generation of novel cationic antimicrobial peptides from natural non-antimicrobial sequences by acid-amide substitution.

Abstract：

BACKGROUND:Cationic antimicrobial peptides (CAMPs) are well recognized to be promising as novel antimicrobial and antitumor agents. To obtain novel skeletons of CAMPs, we propose a simple strategy using acid-amide substitution (i.e. Glu→Gln, Asp→Asn) to confer net positive charge to natural non-antimicrobial sequences that have structures distinct from known CAMPs. The potential of this strategy was verified by a trial study. METHODS:The pro-regions of nematode cecropin P1-P3 (P1P-P3P) were selected as parent sequences. P1P-P3P and their acid-amide-substituted mutants (NP1P-NP3P) were chemically synthesized. Bactericidal and membrane-disruptive activities of these peptides were evaluated. Conformational changes were estimated from far-ultraviolet circular dichroism (CD) spectra. RESULTS:NP1P-NP3P acquired potent bactericidal activities via membrane-disruption although P1P-P3P were not antimicrobial. Far-ultraviolet CD spectra of NP1P-NP3P were similar to those of their parent peptides P1P-P3P, suggesting that NP1P-NP3P acquire microbicidal activity without remarkable conformational changes. NP1P-NP3P killed bacteria in almost parallel fashion with their membrane-disruptive activities, suggesting that the mode of action of those peptides was membrane-disruption. Interestingly, membrane-disruptive activity of NP1P-NP3P were highly diversified against acidic liposomes, indicating that the acid-amide-substituted nematode cecropin pro-region was expected to be a unique and promising skeleton for novel synthetic CAMPs with diversified membrane-discriminative properties. CONCLUSIONS:The acid-amide substitution successfully generated some novel CAMPs in our trial study. These novel CAMPs were derived from natural non-antimicrobial sequences, and their sequences were completely distinct from any categories of known CAMPs, suggesting that such mutated natural sequences could be a promising source of novel skeletons of CAMPs.

journal_name

Ann Clin Microbiol Antimicrob

journal_title

Annals of clinical microbiology and antimicrobials

authors

Ueno S,Minaba M,Nishiuchi Y,Taichi M,Tamada Y,Yamazaki T,Kato Y

doi

10.1186/1476-0711-10-11

subject

Has Abstract

pub_date

2011-03-22 00:00:00

pages

issn

1476-0711

pii

1476-0711-10-11

journal_volume

pub_type

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Generation of novel cationic antimicrobial peptides from natural non-antimicrobial sequences by acid-amide substitution.