title: Trivalent ultrashort lipopeptides are potent pH dependent antifungal agents.
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.
authors.affiliation: Department of Biological Chemistry, The Weizmann Institute of Science, Ullman Building, Rehovot 76100, Israel.
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Arnusch
authors.forename: H Bauke
authors.initials: HB
authors.lastname: Albada
authors.forename: Martin
authors.initials: M
authors.lastname: van Vaardegem
authors.forename: Rob M J
authors.initials: RM
authors.lastname: Liskamp
authors.forename: Hans-Georg
authors.initials: HG
authors.lastname: Sahl
authors.forename: Yana
authors.initials: Y
authors.lastname: Shadkchan
authors.forename: Nir
authors.initials: N
authors.lastname: Osherov
authors.forename: Yechiel
authors.initials: Y
authors.lastname: Shai
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000935:Antifungal Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D023181:Antimicrobial Cationic Peptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001232:Aspergillus fumigatus / Q000187:drug effects; D002176:Candida albicans / Q000187:drug effects; D002460:Cell Line; D003455:Cryptococcus neoformans / Q000187:drug effects; D005260:Female; D006090:Gram-Negative Bacteria / Q000187:drug effects; D006094:Gram-Positive Bacteria / Q000187:drug effects; D006461:Hemolysis; D006801:Humans; D006863:Hydrogen-Ion Concentration; D055666:Lipopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008168:Lung / Q000382:microbiology; D051379:Mice; D008813:Mice, Inbred ICR; D008826:Microbial Sensitivity Tests; D049329:Nanostructures; D011108:Polymers; D055732:Pulmonary Aspergillosis / Q000188:drug therapy / Q000382:microbiology; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D000935:Antifungal Agents; D023181:Antimicrobial Cationic Peptides; D055666:Lipopeptides; D011108:Polymers