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The antimicrobial activity of chemerin-derived peptide p4 requires oxidative conditions.

ABSTRACT: Chemerin is a leukocyte attractant, adipokine, and antimicrobial protein abundantly produced in the skin epidermis. Despite the fact that most of the bactericidal activity present in human skin exudates is chemerin-dependent, just how chemerin shapes skin defenses remains obscure. Here we demonstrate that p4, a potent antimicrobial human chemerin peptide derivative, displays killing activity against pathogenic methicillin-resistant Staphylococcus aureus strains and suppresses microbial growth in a topical skin infection model. Mechanistically, we show that p4 homodimerization is required for maximal bactericidal activity and that an oxidative environment, such as at the skin surface, facilitates p4 disulfide bridge formation, required for the dimerization. p4 led to rapid damage of the bacterial internal membrane and inhibited the interaction between the membranous cytochrome bc 1 complex and its redox partner, cytochrome c These results suggest that a chemerin p4-based defense strategy combats bacterial challenges at the skin surface.

SUBMITTER: Godlewska U

PROVIDER: S-EPMC6349111 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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The antimicrobial activity of chemerin-derived peptide p4 requires oxidative conditions.

Godlewska Urszula U Bilska Bernadetta B Zegar Aneta A Brzoza Piotr P Borek Arkadiusz A Murzyn Krzysztof K Bochenska Oliwia O Morytko Agnieszka A Kuleta Patryk P Kozik Andrzej A Pyza Elzbieta E Osyczka Artur A Zabel Brian A BA Cichy Joanna J

The Journal of biological chemistry 20181130 4

Chemerin is a leukocyte attractant, adipokine, and antimicrobial protein abundantly produced in the skin epidermis. Despite the fact that most of the bactericidal activity present in human skin exudates is chemerin-dependent, just how chemerin shapes skin defenses remains obscure. Here we demonstrate that p4, a potent antimicrobial human chemerin peptide derivative, displays killing activity against pathogenic methicillin-resistant <i>Staphylococcus aureus</i> strains and suppresses microbial gr ...[more]

PMID: 30504221

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Project description:BackgroundThe antibiotic resistance and biofilm formation of pathogenic microbes exacerbate the difficulties of anti-infection therapy in the clinic. The structural modification of antimicrobial peptides (AMP) is an effective strategy to develop novel anti-infective agents.MethodSeventeen amino acids (AA) in the longer chain of EeCentrocin 1 (from the edible sea-urchin Echinus esculentus) were truncated and underwent further modification. To produce lead peptides with low toxicity and high efficacy, the antimicrobial activity or cytotoxicity of peptides was evaluated against various multidrug-resistant bacteria/fungi or mammalian cells in vivo/ in vitro. In addition, the stability and modes of action of the lead peptide were investigated.FindingsEC1-17KV displayed potent activity and an expanded antimicrobial spectrum, especially against drug-resistant gram-negative bacteria and fungi, attributable to its enhanced amphiphilicity and net charge. In addition, it exhibits bactericidal/fungicidal activity and effectively increased the animal survival rate and mitigated the histopathological damage induced by multidrug-resistant P. aeruginosa or C. albicans in infected mice or G. mellonella. Moreover, EC1-17KV had a poor ability to induce resistance in bacteria and fungi and exhibited desirable high-salt/high-temperature tolerance properties. In bacteria, EC1-17KV promoted divalent cation release to damage bacterial membrane integrity. In fungi, it changed C. albicans membrane fluidity to increase membrane permeabilization or reduced hyphal formation to suppress biofilm formation.InterpretationEC1-17KV is a promising lead peptide for the development of antimicrobial agents against antibiotic resistant bacteria and fungi.FundingThis work was funded by the National Natural Science Foundation of China (No. 81673483, 81803591); National Science and Technology Major Project Foundation of China (2019ZX09721001-004-005); National Key Research and Development Program of China (2018YFA0902000); "Double First-Class" University project (CPU2018GF/GY16); Natural Science Foundation of Jiangsu Province of China (No. BK20180563); and A Project Funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions.

Dataset Information

The antimicrobial activity of chemerin-derived peptide p4 requires oxidative conditions.

Publications

The antimicrobial activity of chemerin-derived peptide p4 requires oxidative conditions.

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