With the emergence of pathogens resistant to conventional antimicrobials, and toxicity of some antimycotics, there is an urgent need for development of new agents with novel mechanisms of action. One promising source is cationic antimicrobial peptides. We have discovered that human salivary mucin MUC7 peptides (derived from the N-terminus) possess significant and broad-spectrum antimicrobial activity m vitro. These cationic peptides are effective against a variety of fungi (e.g., C. albicans and C. neoformans, organisms responsible for the common opportunistic infections in immunocompromised patients, particularly those with HIV/AIDS), and both Gram-positive and negative bacteria (e.g. S. mutans, implicated in dental caries and P. gingivalis, implicated in periodontal diseases). MUC7 20-mer and 12-mer retain considerable candidacidal activity in physiological-like conditions found in the oral cavity. The 12-mer in combination with histatin-5-12-mer or amphotericin-B acts in a synergistic or additive manner against C. albicans and C. neoformans. A newest addition, 12-mer-D isomer exhibits more potent candidacidal activity in high-ionic strength buffers and in saliva, and is less hemolytic than the 12-mer-L (natural form). These finding support and strengthen our hypothesis that these novel peptides are indeed suitable candidates for therapeutic and preventive antimicrobials. Further, that they will show little or no toxicity toward mammalian cells and will have low tendency to elicit resistance. The work proposed in this application will further evaluate the MUC7 peptide potential as therapeutic agents in vitro and m vivo, and continue to examine their mechanism of action.
In Specific Aim 1, MUC7 12-mer peptide antimicrobial activity will be examined in detail, including in combination with other antimicrobial agents.
In Specific Aim 2, we will address the mechanism of MUC7 peptide action, including intracellular target(s), potential binding to nucleic acid, inhibition of protein and nucleic acid synthesis, and the effect of MUC7 peptide on C. albicans and S. cerevisiae by gene expression profiling.
Specific Aim 3 will address the formulation and in vitro testing of biodegradable polymeric and/or hydrogel polymeric delivery systems for these peptides.
In Specific Aim 4, we will test the efficacy of the specifically design delivery systems against fungal infections in vivo models. Altogether, these efforts attempt to move the MUC7 peptides toward the long-range goal of clinical application.
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