Structural determinants of host defense peptides for antimicrobial activity and target cell selectivity

The development of new therapeutic options against Clostridioides difficile (C. difficile) infection is a critical public health concern, as the causative bacterium is highly resistant to multiple classes of antibiotics. Antimicrobial host-defense peptides (HDPs) are highly effective at simultaneously modulating the immune system function and directly killing bacteria through membrane disruption and oxidative damage. The copper-binding HDPs piscidin 1 and piscidin 3 have previously shown potent antimicrobial activity against a number of Gram-negative and Gram-positive bacterial species but have never been investigated in an anaerobic environment. Synergy between piscidins and metal ions increases bacterial killing aerobically. Here, we performed growth inhibition and time-kill assays against C. difficile showing that both piscidins suppress proliferation of C. difficile by killing bacterial cells. Microscopy experiments show that the peptides accumulate at sites of membrane curvature. We find that both piscidins are effective against epidemic C. difficile strains that are highly resistant to other stresses. Notably, copper does not enhance piscidin activity against C. difficile. Thus, while antimicrobial activity of piscidin peptides is conserved in aerobic and anaerobic settings, the peptide–copper interaction depends on environmental oxygen to achieve its maximum potency. The development of pharmaceuticals from HDPs such as piscidin will necessitate consideration of oxygen levels in the targeted tissue.

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Structure-Activity Studies and Therapeutic Potential of Host Defense Peptides of Human Thrombin

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01515-10 ◽

2011 ◽

Vol 55 (6) ◽

pp. 2880-2890 ◽

Cited By ~ 46

Author(s):

Gopinath Kasetty ◽

Praveen Papareddy ◽

Martina Kalle ◽

Victoria Rydengård ◽

Matthias Mörgelin ◽

...

Keyword(s):

Amino Acids ◽

Antimicrobial Activity ◽

Host Defense ◽

Host Defense Peptides ◽

Content Type ◽

Peptide Epitopes ◽

Structure Activity ◽

Human Thrombin ◽

Defense Peptides ◽

Anti Inflammatory

ABSTRACTPeptides of the C-terminal region of human thrombin are released upon proteolysis and identified in human wounds. In this study, we wanted to investigate minimal determinants, as well as structural features, governing the antimicrobial and immunomodulating activity of this peptide region. Sequential amino acid deletions of the peptide GKYGFYTHVFRLKKWIQKVIDQFGE (GKY25), as well as substitutions at strategic and structurally relevant positions, were followed by analyses of antimicrobial activity against the Gram-negative bacteriaEscherichia coliandPseudomonas aeruginosa, the Gram-positive bacteriumStaphylococcus aureus, and the fungusCandida albicans. Furthermore, peptide effects on lipopolysaccharide (LPS)-, lipoteichoic acid-, or zymosan-induced macrophage activation were studied. The thrombin-derived peptides displayed length- and sequence-dependent antimicrobial as well as immunomodulating effects. A peptide length of at least 20 amino acids was required for effective anti-inflammatory effects in macrophage models, as well as optimal antimicrobial activity as judged by MIC assays. However, shorter (>12 amino acids) variants also displayed significant antimicrobial effects. A central K14 residue was important for optimal antimicrobial activity. Finally, one peptide variant, GKYGFYTHVFRLKKWIQKVI (GKY20) exhibiting improved selectivity, i.e., low toxicity and a preserved antimicrobial as well as anti-inflammatory effect, showed efficiency in mouse models of LPS shock andP. aeruginosasepsis. The work defines structure-activity relationships of C-terminal host defense peptides of thrombin and delineates a strategy for selecting peptide epitopes of therapeutic interest.

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Human hemoglobin-derived peptides exhibit antimicrobial activity: a class of host defense peptides

Journal of Chromatography B ◽

10.1016/s1570-0232(03)00245-9 ◽

2003 ◽

Vol 791 (1-2) ◽

pp. 345-356 ◽

Cited By ~ 83

Author(s):

Cornelia Liepke ◽

Susann Baxmann ◽

Cornelia Heine ◽

Nicole Breithaupt ◽

Ludger Ständker ◽

...

Keyword(s):

Antimicrobial Activity ◽

Host Defense ◽

Human Hemoglobin ◽

Host Defense Peptides ◽

Defense Peptides

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Relationship between amino acid sequence diversity and antimicrobial activity of Japanese quail cathelicidins

10.21203/rs.2.14418/v1 ◽

2019 ◽

Author(s):

Taichiro Ishige ◽

Hiromi HARA ◽

Takashi HIRANO ◽

Tomohiro KONO ◽

Kei HANZAWA

Keyword(s):

Antimicrobial Activity ◽

Antibacterial Activity ◽

Amino Acid ◽

Host Defense ◽

Japanese Quail ◽

Bird Species ◽

Amino Acid Substitutions ◽

Host Defense Peptides ◽

Genomic Analyses ◽

Defense Peptides

Abstract Background Japanese quail is a low-fat, meat-bird species exhibiting high disease resistance. Cathelicidins (CATHs) are host defense peptides conserved across numerous vertebrate species that play an important role in innate immunity. The activity of host defense peptides can be affected by amino acid substitutions. However, no polymorphisms in avian CATH genes have been reported to date. The aim of this study was to clarify the effect on antimicrobial activity of polymorphisms in CATHs. Results DNA for genomic analyses was extracted from the peripheral blood of 99 randomly selected quail from 6 inbred lines. A total of six, four, four, and six CjCATH3 , CjCATH2 , CjCATHB1 , and CjCATH1 alleles were identified, respectively. Nine haplotypes, including four that were strain specific, were identified in alleles from the CjCATH3 , CjCATH2 , CjCATHB1 , and CjCATH1 loci. In addition, two and one amino acid substitutions (I145F, Q148H, and P245H) predicted by PROVEAN and PolyPhen-2 to have deleterious effects were detected at CjCATH2 and B1, respectively. Synthetic CjCATH2 and B1 peptides exhibited greater antibacterial activity against Escherichia coli than chicken CATH2 and B1, respectively. Furthermore, CjCATHB1*04 peptide exhibited less-potent antimicrobial activity than other CjCATHB1 peptides examined. Conclusions This is the first report of amino acid substitutions accompanied by changes in antibacterial activity in avian CATHs. These findings could be employed as indicators of improvements in the innate immune response in poultry.

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Outer Membrane Vesicles Protect Gram-Negative Bacteria against Host Defense Peptides

mSphere ◽

10.1128/msphere.00523-21 ◽

2021 ◽

Author(s):

Melanie D. Balhuizen ◽

Albert van Dijk ◽

Jeroen W. A. Jansen ◽

Chris H. A. van de Lest ◽

Edwin J. A. Veldhuizen ◽

...

Keyword(s):

Antimicrobial Activity ◽

Antibiotic Resistance ◽

Host Defense ◽

Membrane Vesicles ◽

Outer Membrane Vesicles ◽

Gram Negative Bacteria ◽

Host Defense Peptides ◽

Resistance Development ◽

Gram Negative ◽

Defense Peptides

Antibiotic resistance is a pressing problem and estimated to be a leading cause of mortality by 2050. Antimicrobial peptides, also known as host defense peptides (HDPs), and HDP-derived antimicrobials have potent antimicrobial activity and high potential as alternatives to antibiotics due to low resistance development.

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