Trivalent ultrashort lipopeptides are potent pH dependent antifungal agents

Christopher J. Arnusch, H. Bauke Albada, Martin Van Vaardegem, Rob M.J. Liskamp, Hans Georg Sahl, Yana Shadkchan, Nir Osherov, Yechiel Shai

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

The activity of antimicrobial peptides (AMPs) that contain a large proportion of histidine residues (pK a ∼ 6) depends on the physiological pH environment. Advantages of these AMPs include high activity in slightly acidic areas of the human body and relatively low toxicity in other areas. Also, many AMPs are highly active in a multivalent form, but this often increases toxicity. Here we designed pH dependent amphiphilic compounds consisting of multiple ultrashort histidine lipopeptides on a triazacyclophane scaffold, which showed high activity toward Aspergillus fumigatus and Cryptococcus neoformans at acidic pH, yet remained nontoxic. In vivo, treatment with a myristic acid conjugated trivalent histidine-histidine dipeptide resulted in 55% survival of mice (n = 9) in an otherwise lethal murine lung Aspergillus infection model. Fungal burden was assessed and showed completely sterile lungs in 80% of the mice (n = 5). At pH 5.5 and 7.5, differing peptide-membrane interactions and peptide nanostructures were observed. This study underscores the potential of unique AMPs to become the next generation of clinical antimicrobial therapy.

Original languageEnglish
Pages (from-to)1296-1302
Number of pages7
JournalJournal of Medicinal Chemistry
Volume55
Issue number3
DOIs
StatePublished - 9 Feb 2012
Externally publishedYes

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