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Dermatophytic defensin with antiinfective potential.

ABSTRACT: Fungi are a newly emerging source of peptide antibiotics with therapeutic potential. Here, we report 17 new fungal defensin-like peptide (fDLP) genes and the detailed characterization of a corresponding synthetic fDLP (micasin) from a dermatophyte in terms of its structure, activity and therapeutic potential. NMR analysis showed that synthetic micasin adopts a "hallmark" cysteine-stabilized α-helical and β-sheet fold. It was active on both gram-positive and gram-negative bacteria, and importantly it killed two clinical isolates of methicillin-resistant Staphylococcus aureus and the opportunistic pathogen Pseudomonas aeruginosa at low micromolar concentrations. Micasin killed approximately 100% of treated bacteria within 3 h through a membrane nondisruptive mechanism of action, and showed extremely low hemolysis and high serum stability. Consistent with these functional properties, micasin increases survival in mice infected by the pathogenic bacteria in a peritonitis model. Our work represents a valuable approach to explore novel peptide antibiotics from a large resource of fungal genomes.

SUBMITTER: Zhu S

PROVIDER: S-EPMC3365176 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Dermatophytic defensin with antiinfective potential.

Zhu Shunyi S Gao Bin B Harvey Peta J PJ Craik David J DJ

Proceedings of the National Academy of Sciences of the United States of America 20120514 22

Fungi are a newly emerging source of peptide antibiotics with therapeutic potential. Here, we report 17 new fungal defensin-like peptide (fDLP) genes and the detailed characterization of a corresponding synthetic fDLP (micasin) from a dermatophyte in terms of its structure, activity and therapeutic potential. NMR analysis showed that synthetic micasin adopts a "hallmark" cysteine-stabilized α-helical and β-sheet fold. It was active on both gram-positive and gram-negative bacteria, and importantl ...[more]

PMID: 22586077

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Project description:ObjectiveThis work focuses on tackling the inadequate bone/implant interface strength of acrylic bone cements, which is a formidable problem diminishing their clinical performance, especially in percutaneous kyphoplasty surgery.MethodsA new strategy of incorporating magnesium particles into clinically used poly(methylmethacrylate) (PMMA) bone cement to prepare a surface-degradable bone cement (SdBC) is proposed and validated both in vitro and in vivo.ResultsThis surface degradation characteristic enables osseointegrative, angiogenic and antiinfective properties. SdBC showed fast surface degradation and formed porous surfaces as designed, while the desirable high compressive strengths (≥70 MPa) of the cement were preserved. Besides, the SdBC with proper Mg content promoted osteoblast adhesion, spreading, proliferation and endothelial cell angiogenesis capacity compared with PMMA. Also, SdBC demonstrated clear inhibitory effect on Staphylococcus aureus and Escherichia coli. In vivo evaluation on SdBC by the rat femur defect model showed that the bone/implant interface strength was significantly enhanced in SdBC (push-out force of 11.8 ± 1.5 N for SdBC vs 7.0 ± 2.3N for PMMA), suggesting significantly improved osseointegration and bone growth induced by the surface degradation of the cement. The injectability, setting times and compressive strengths of SdBC with proper content of Mg particles (2.8 wt% and 5.4 wt%) were comparable with those of the clinical acrylic bone cement, while the heat release during polymerization was reduced (maximum temperature 78 ± 1 °C for PMMA vs 73.3 ± 1.5 °C for SdBC).ConclusionsThis work validates a new concept of designing bioactive bone/implant interface in PMMA bone cement. And this surface-degradable bone cement possesses great potential for minimally invasive orthopaedic surgeries such as percutaneous kyphoplasty.The translational potential of this articleThis work reports PMMA/Mg surface-degradable acrylic bone cements that possess enhanced osseointegrative, angiogenic and antiinfective properties that are lacking in the clinically used acrylic bone cements. This new kind of bone cements could improve the treatment outcome of many orthopaedic surgeries such as percutaneous kyphoplasty and arthroplasty.

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Dermatophytic defensin with antiinfective potential.

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Dermatophytic defensin with antiinfective potential.

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