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Cathelicidin Antimicrobial Peptides with Reduced Activation of Toll-Like Receptor Signaling Have Potent Bactericidal Activity against Colistin-Resistant Bacteria

Cathelicidin Antimicrobial Peptides with Reduced Activation of Toll-Like Receptor Signaling Have Potent Bactericidal Activity against Colistin-Resistant Bacteria

Authors :
Cheng Kao
Xiaoyan Lin
Guanghui Yi
Yunliang Zhang
Dean A. Rowe-Magnus
Karen Bush
Source :
mBio, Vol 7, Iss 5 (2016)
Publication Year :
2016
Publisher :
American Society for Microbiology, 2016.

Abstract

ABSTRACT The world is at the precipice of a postantibiotic era in which medical procedures and minor injuries can result in bacterial infections that are no longer effectively treated by antibiotics. Cathelicidins are peptides produced by animals to combat bacterial infections and to regulate innate immune responses. However, cathelicidins are potent activators of the inflammatory response. Cathelicidins with reduced proinflammatory activity and potent bactericidal activity in the low micromolar range against Gram-negative bacteria have been identified. Motifs in cathelicidins that impact bactericidal activity and cytotoxicity to human cells have been elucidated and used to generate peptides that have reduced activation of proinflammatory cytokine production and reduced cytotoxicity to human cells. The resultant peptides have bactericidal activities comparable to that of colistin and can kill colistin-resistant bacteria. IMPORTANCE Cathelicidins are antimicrobial peptides that can also increase inflammatory responses. This combination of activities can cause complications in the treatment of bacterial infections despite the pressing need for new antimicrobials. We have identified cathelicidins with decreased activation of inflammatory responses. The peptides kill Gram-negative bacteria at low micromolar concentrations by binding to and perturbing the integrity of the bacterial membrane. The peptides were also engineered to further decrease lysis of human red blood cells. The peptides have activities comparable to those of the polymyxins, a class of antibiotics to which plasmid-borne resistance is rapidly spreading and can kill colistin-resistant bacteria. These peptides are promising candidates for the development of novel antibacterial agents.

Subjects

Subjects :
Microbiology
QR1-502

Details

Language :
English
ISSN :
21507511
Volume :
7
Issue :
5
Database :
Directory of Open Access Journals
Journal :
mBio
Publication Type :
Academic Journal
Accession number :
edsdoj.fdf085814beaaa83ce5dfbefb490
Document Type :
article
Full Text :
https://doi.org/10.1128/mBio.01418-16