Characterization and functional analysis of cathelicidin-MH, a novel frog-derived peptide with anti-septicemic properties.
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ABSTRACT:
SUBMITTER: Chai J
PROVIDER: S-EPMC8057816 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:(PA) is the leading cause of corneal blindness worldwide. A constant increase in multi-drug resistant PA strains have heightened the challenge of effectively managing corneal infections with conventional antibiotics. Antimicrobial peptides are promising antibiotic analogs with a unique mode of action. Cathelicidin-derived shorter peptides (FK13 and FK16) have previously been shown to kill a range of pathogens in both and systems. Here, our aim was to exploit the potential of FK13 or FK16 to enhance the anti- activity of vancomycin, which normally has low clinical efficacy against PA. Our results have demonstrated that FK16 is more potent than FK13 against different PA strains including a clinical isolate from a patient’s ocular surface. FK16 was shown to enhance the membrane permeability of PAO1 at sub-inhibitory concentrations. Moreover, FK16 at lower concentrations was shown to increase the antibacterial susceptibility of vancomycin against PA strains up to eightfold. The bactericidal synergism between FK16 and vancomycin was shown to be stable in the presence of physiological tear salt concentration and did not cause toxic effects on the human corneal epithelial cells and human red blood cells. Our results have revealed that sub-inhibitory concentration of FK16 could augment the antimicrobial effects of vancomycin against PA. It is anticipated that the future exploitation of the peptide design approach may enhance the effectiveness of FK16 and its application as an adjuvant to antibiotic therapy for the treatment of multi-drug resistant infections.
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Project description:Host Defence Peptides and derived peptides are promising classes of antimicrobial and immunomodulatory lead compounds. For this purpose we examined whether chicken cathelicidin-2 (CATH-2)-derived peptides modulate the function and inflammatory response of avian immune cells. Using a chicken macrophage cell line (HD11) we found that full-length CATH-2 dose-dependently induced transcription of chemokines CXCLi2/IL-8, MCP-3 and CCLi4/RANTES, but not of pro-inflammatory cytokine IL-1?. In addition, CATH-2 efficiently inhibited IL-1? and nitric oxide production by HD11 cells induced by different sources of lipopolysaccharides (LPS). N-terminal truncated CATH-2 derived peptides maintained the capacity to selectively induce chemokine transcription, but despite their high LPS affinity several analogs lacked LPS-neutralizing capacity. Substitution of phenylalanine residues by tryptophan introduced endotoxin neutralization capacity in inactive truncated CATH-2 derived peptides. In contrast, amino acid substitution of phenylalanine by tyrosine abrogated endotoxin neutralization activity of CATH-2 analogs. These findings support a pivotal role for aromatic residues in peptide-mediated endotoxin neutralization by CATH-2 analogs and were shown to be independent of LPS affinity. The capacity to modulate chemokine production and dampen endotoxin-induced pro-inflammatory responses in chicken immune cells implicates that small CATH-2 based peptides could serve as leads for the design of CATH-2 based immunomodulatory anti-infectives.
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Project description:Cecropins, originally found in insects, are a group of cationic antimicrobial peptides. Most cecropins have an amphipathic N-terminal segment and a largely hydrophobic C-terminal segment, and normally form a helix-hinge-helix structure. In this study, we developed the novel 32-residue cecropin-like peptide cecropin DH by deleting the hinge region (Alanine-Glycine-Proline) of cecropin B isolated from Chinese oak silk moth, Antheraea pernyi. Cecropin DH possesses effective antibacterial activity, particularly against Gram-negative bacteria, with very low cytotoxicity against mammalian cells. Interactions between cecropin DH and the highly anionic lipopolysaccharide (LPS) component of the Gram-negative bacterial outer membrane indicate that it is capable of dissociating LPS micelles and disrupting LPS aggregates into smaller assemblies, which may play a vital role in its antimicrobial activity. Using LPS-stimulated mouse macrophage RAW264.7 cells, we found that cecropin DH exerted higher potential anti-inflammatory activity than cecropin B, as demonstrated by the inhibition of pro-inflammatory cytokines nitric oxide production and secretion of tumor necrosis factor-α. In conclusion, cecropin DH has potential as a therapeutic agent for both antibacterial and anti-inflammatory applications.
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Project description:LL-37 is the only cathelicidin-derived polypeptide found in humans. Its eclectic function makes this peptide one of the most intriguing chemical defense agents, with crucial roles in moderating inflammation, promoting wound healing, and boosting the human immune system. LL-37 kills both prokaryotic and eukaryotic cells through physical interaction with cell membranes. In order to study its active conformation in membranes, we have reconstituted LL-37 into dodecylphosphocholine (DPC) micelles and determined its three-dimensional structure. We found that, under our experimental conditions, this peptide adopts a helix-break-helix conformation. Both the N- and C-termini are unstructured and solvent exposed. The N-terminal helical domain is more dynamic, while the C-terminal helix is more solvent protected and structured (high density of NOEs, slow H/D exchange). When it interacts with DPC, LL-37 is adsorbed on the surface of the micelle with the hydrophilic face exposed to the water phase and the hydrophobic face buried in the micelle hydrocarbon region. The break between the helices is positioned at K12 and is probably stabilized by a hydrophobic cluster formed by I13, F17, and I20 in addition to a salt bridge between K12 and E16. These results support the proposed nonpore carpet-like mechanism of action, in agreement with the solid-state NMR studies, and pave the way for understanding the function of the mature LL-37 at the atomic level.
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Project description:The emergence of antimicrobial resistance among pathogenic microorganisms has been led to an urgent need for antibiotic alternatives. Antimicrobial peptides (AMPs) have been introduced as promising therapeutic agents because of their remarkable potentials. A new modified cathelicidin-BF peptide (Cath-A) with 34 amino acid sequences, represents the potential antimicrobial effects against methicillin-resistant Staphylococcus aureus (MRSA) with slight hemolytic and cytotoxic activities on eukaryotic cells. In this study, the effects of Cath-A on Acinetobacter baumannii, and Pseudomonas aeruginosa isolated from medical instruments were studied. Cath-A inhibited the growth of bacterial cells in the range of 8⁻16 μg/mL and 16-≥256 μg/mL for A. baumannii and P. aeruginosa, respectively. The peptide significantly removed the established biofilms. To display a representative approach for the cost-effective constructions of peptides, the recombinant Cath-A was cloned in the expression vector pET-32a(+) and transformed to Escherichia coli BL21. The peptide was expressed with a thioredoxin (Trx) sequence in optimum conditions. The recombinant peptide was purified with a Ni2+ affinity chromatography and the mature peptide was released after removing the Trx fusion protein with enterokinase. The final concentration of the partially purified peptide was 17.6 mg/L of a bacterial culture which exhibited antimicrobial activities. The current expression and purification method displayed a fast and effective system to finally produce active Cath-A for further in-vitro study usage.
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Project description:Lung cancer is the major cause of cancer deaths worldwide, and it has the highest incidence and mortality rate of any cancer among men and women in China. The first-line therapy for lung cancer treatment is platinum-based chemotherapy drugs such as cisplatin. However, the application of present chemotherapies is limited by severe side effects, which stimulates the discovery of new drugs with new anti-tumor mechanisms and fewer side effects. Beneficially, many antimicrobial peptides (AMPs) from frog skin have been reported to exhibit potent anti-cancer activities with low toxicity, high selectivity and a low propensity to induce resistance. In this study, we first reported an AMP named Dermaseptin-PP, from a rarely studied frog species, Phyllomedusa palliata. Dermaseptin-PP exhibited selective cytotoxicity on H157, MCF-7, PC-3, and U251 MG cancer cells instead of normal HMEC-1 cells with low hemolytic effect. Furthermore, on subcutaneous H157 tumor model of nude mice, Dermaseptin-PP was found to display potent in vivo anti-tumor activity in a dose-related manner without obvious hepatopulmonary side effects. It is widely accepted that AMPs usually work through a membrane disruptive mode, and the confocal laser microscope observation confirmed that Dermaseptin-PP could destroy H157 cell membranes. Further investigation of mechanisms by flow cytometry assay and immunohistochemical analysis unraveled that Dermaseptin-PP also exerted its anti-tumor activity by inducing H157 cell apoptosis via both endogenous mitochondrial apoptosis pathway and exogenous death receptor apoptosis pathway. Herein, we emphasize that the membrane disrupting and the apoptosis activation effects of Dermaseptin-PP both depend on its concentration. Overall, a novel frog skin-derived AMP, named Dermaseptin-PP, was identified for the first time. It possesses strong antimicrobial activity and effective anti-tumor activity by distinct mechanisms. This study revealed the possibility of Dermaseptin-PP for lung cancer treatment and provided a new perspective for designing novel AMP-based anti-tumor candidates with low risk of cytotoxicity.
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