AAC Accepts, published online ahead of print on 7 July 2008

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Antimicrob. Agents Chemother. doi:10.1128/AAC.00526-08
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Efficient Clearance of Aspergillus Fumigatus By an Ultrashort Anti-Microbial Lipopeptide Palmitoyl-Lys-Ala-dAla-Lys In Murine Lungs

Alexandra Vallon-Eberhard, Arik Makovitzki, Anne Beauvais, Jean-Paul Latgé, Steffen Jung, and Yechiel Shai^*

Department of Immunology, and Department of Biological Chemistry, Weizmann Institute of Science, 76100 Rehovot, Israel; Unité des Aspergillus, Institut Pasteur, Paris, France

^* To whom correspondence should be addressed. Email: Yechiel.Shai{at}weizmann.ac.il.

Aspergillus fumigatus is an opportunistic fungal pathogen responsible for invasive aspergillosis in immuno-compromised individuals. The inefficiency of antifungal agents and high mortality rate resulting from invasive aspergillosis remain a major clinical concern. Recently, we have reported on a new family of ultrashort cationic lipopeptides active in vitro against fungi. Mode of action studies supported a membranolytic or a detergent-like effect. Here we screened several lipopeptides in vitro for their anti-Aspergillus fumigatus activity. To investigate the therapeutic properties of the selected peptides in vivo, we challenged immuno-suppressed C57BL/6 wt mice intra-nasally with DsRed-labeled A. fumigatus conidia and subsequently treated the animals locally with the lipopeptides. Confocal microscopic analysis revealed the degradation of DsRed-labeled hyphal forms and residual conidia in the lungs of the mice. The most efficient peptide was further tested in a survival assay and was found to significantly prolong the life of the treated animals, whereas no mice survived with the current standard antifungal treatment with amphotericin B. Moreover as opposed to the drug-treated lungs, peptide-treated lungs did not display any toxicity of the peptide. Our results highlight the potential of this family of lipopeptides in the treatment of pulmonary invasive aspergillosis.

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