Novel anti-infectives: is host defence the answer?

Hamill, Pamela; Brown, Kelly L.; Jenssen, Håvard; Hancock, Robert E. W.

doi:10.1016/j.copbio.2008.10.006

Cited by 80 publications

(72 citation statements)

References 33 publications

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“…As the mode of immunomodulatory action is likely to be independent of interactions with cell membranes, the issues of hemolytic activity and cytotoxicity toward mammalian cells are minimized, as supported by the minimal toxicity of peptide IDR-1 compared with natural cathelicidins like LL-37 (16,19). Furthermore, the many positive feedback systems that operate in the regulation of immune responses allow an immunomodulatory treatment to have wider effects on the outcome of infection than those of a microbicidal drug (20,21), and, indeed, IDR-1 has shown broad-spectrum protective activity in many models of infection (16) (R. E. W. Hancock, unpublished observations). Importantly, many host defense peptides combine both anti-infective and anti-inflammatory activities, and thus, IDR-1 therapy is not associated with risks of inflammatory tissue damage, as is often the case with other immunostimulatory treatments.…”

mentioning

confidence: 99%

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

Nijnik

Madera

et al. 2010

The Journal of Immunology

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With the rapid rise in the incidence of multidrug resistant infections, there is substantial interest in host defense peptides as templates for production of new antimicrobial therapeutics. Natural peptides are multifunctional mediators of the innate immune response, with some direct antimicrobial activity and diverse immunomodulatory properties. We have previously developed an innate defense regulator (IDR) 1, with protective activity against bacterial infection mediated entirely through its effects on the immunity of the host, as a novel approach to anti-infective therapy. In this study, an immunomodulatory peptide IDR-1002 was selected from a library of bactenecin derivatives based on its substantially more potent ability to induce chemokines in human PBMCs. The enhanced chemokine induction activity of the peptide in vitro correlated with stronger protective activity in vivo in the Staphylococcus aureus-invasive infection model, with a >5-fold reduction in the protective dose in direct comparison with IDR-1. IDR-1002 also afforded protection against the Gram-negative bacterial pathogen Escherichia coli. Chemokine induction by IDR-1002 was found to be mediated through a Gi-coupled receptor and the PI3K, NF-κB, and MAPK signaling pathways. The protective activity of the peptide was associated with in vivo augmentation of chemokine production and recruitment of neutrophils and monocytes to the site of infection. These results highlight the importance of the chemokine induction activity of host defense peptides and demonstrate that the optimization of the ex vivo chemokine-induction properties of peptides is a promising method for the rational development of immunomodulatory IDR peptides with enhanced anti-infective activity.

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confidence: 99%

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

Nijnik

Madera

et al. 2010

The Journal of Immunology

Self Cite

186

225

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“…Naturally occurring antimicrobial peptides (AMPs) 3 are found in virtually all living organisms and form a critical part of the innate immune system in mammals, providing protection against pathogen invasion (1,2). More than 1000 different antimicrobial peptides have been documented with activity against viruses, bacteria, and fungi, prompting interest in using the structural principles of small cationic, amphiphilic molecules for improving and fine tuning target specificity and efficacy (3)(4)(5)(6).…”

mentioning

confidence: 99%

“…More than 1000 different antimicrobial peptides have been documented with activity against viruses, bacteria, and fungi, prompting interest in using the structural principles of small cationic, amphiphilic molecules for improving and fine tuning target specificity and efficacy (3)(4)(5)(6). Non-natural multivalent AMPs have been designed by conjugating copies of a peptide monomer to scaffold molecules via naturally occurring intermolecular disulfide bridges or unnatural scaffold linkers (7).…”

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confidence: 99%

Progressive Structuring of a Branched Antimicrobial Peptide on the Path to the Inner Membrane Target

Bai

Liu

et al. 2012

Journal of Biological Chemistry

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Background: A cationic branched peptide was designed with antimicrobial activities against Gram-negative bacteria. Results: B2088 penetrated the outer membrane through inducing phase transitions of LPS and caused inner membrane depolarization by lipid redistribution. Conclusion: Our findings support the interfacial activity model and extend it to more complex interfaces. Significance: We provide a functional structural motif for developing new antimicrobials.

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“…antimicrobial activity and the effectiveness of plant extracts, such as bacteriocins, defence peptides and phenolics has been demonstrated. [19][20][21] Polyphenolic plant derivatives, which are part of a plant's natural defence mechanisms against viral and bacterial pathogens, have been the main focus of investigation. In addition to greater antimicrobial activity and improved safety profiles, there is also a perception that natural agents may be more acceptable to patients.…”

Section: Introductionmentioning

confidence: 99%

Antimicrobial activity of Citrox® bioflavonoid preparations against oral microorganisms

et al. 2011

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Novel anti-infectives: is host defence the answer?

Cited by 80 publications

References 33 publications

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

Synthetic Cationic Peptide IDR-1002 Provides Protection against Bacterial Infections through Chemokine Induction and Enhanced Leukocyte Recruitment

Progressive Structuring of a Branched Antimicrobial Peptide on the Path to the Inner Membrane Target

Antimicrobial activity of Citrox® bioflavonoid preparations against oral microorganisms

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