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Hydramacin-1 is a novel antimicrobial protein recently discoveredÂ during investigations of the epithelial defense of the ancientmetazoanÂ Hydra. The amino acid sequence of hydramacin-1 showsÂ no sequence homology to any known antimicrobial proteins. DeterminationÂ of the solution structure revealed that hydramacin-1 possessesÂ a disulfide bridge-stabilizedÂ Î² motif. This motif is theÂ common scaffold of the knottin protein fold. The structurallyÂ closest relatives are the scorpion oxin-like superfamily. Withinthis superfamily hydramacin-1 establishes a new family of proteinsÂ that all share antimicrobial activity.
Hydramacin-1 is potently active against Gram-positive and Gram-negativeÂ bacteria including multi-resistant human pathogenic strains.Â It leads to aggregation of bacteria as an initial step of itsÂ bactericidal mechanism. Aggregated cells are connected via electron-denseÂ contacts and adopt a thorn apple-like morphology. Analysis ofÂ the hydramacin-1 structure revealed an unusual distributionÂ of amino acid side chains on the surface. A belt of positivelyÂ charged residues is sandwiched by two hydrophobic areas. BasedÂ on this characteristic surface feature and on biophysical analysisÂ of protein-membrane interactions, we propose a model that describesÂ the aggregation effect exhibited by hydramacin-1