Our bodies are constantly exposed to potentially harmful microbes which could cause disease unless prevented by host defense mechanisms. Antimicrobial polypeptides (AMPs) constitute an important part of the innate immune system and have a direct antimicrobial effect, and often additional roles as growth factors and in inflammation. Midkine (MK) is a heparin-binding growth factor with a structure similar to b-defensins, a known AMP. Could MK work as an AMP? Using viable count assay we've shown MK to display strong antibacterial activity against both gram-positive and gram-negative bacteria. Electronmicroscopy and experiments using artificial lipid-bilayers, suggest that MK exert the antibacterial action via membrane disruptive mechanisms.

MK consists of two domains and the antibacterial activity was mapped to the unordered COOH-terminal tail and the last b-sheets of the NH2-terminal. Analysis of highly conserved MK orthologues suggests antibacterial activity in corresponding domains. In support of an evolutionary conserved function, the most distant orthologue, Miple2 from the insect Drosophila melanogaster, also displayed strong antibacterial activity. MK is expressed by keratinocytes of the skin and is also present at the site of infection during fungal dermatitis. In addition to the antibacterial role of MK we investigated possible antifungal activity. MK had high antifungal activity against both Candida albicans and Candida parapsilosis at physiological salt-concentrations. MK affected liposomes with ergosterol more greatly than liposomes with cholesterol, meaning that MK preferentially disrupt fungal rather than host membranes. These findings suggest that MK, in addition to earlier described activities, may have important roles as an innate antibiotic.