title: Synergistic antifungal activity of KB425796-C in combination with micafungin against Aspergillus fumigatus and its efficacy in murine infection models.
abstract: KB425796-C is a novel antifungal metabolite produced by the newly isolated bacterial strain Paenibacillus sp. No. 530603. This compound is a 40-membered macrocyclic lipopeptidolactone consisting of 12 amino acids and a 3-hydroxy-15-methylpalmitoyl moiety. KB425796-C displayed antifungal activity against micafungin-resistant fungi and was fungicidal to Trichosporon asahii in vitro. In a murine systemic infection model of T. asahii, KB425796-C showed excellent efficacy upon i.p. administration at 32 mg kg(-1). In addition, KB425796-C induced morphological changes in the hyphae of Aspergillus fumigatus and had fungicidal effects in combination with micafungin. In a mouse model of septic A. fumigatus infection, although non-treated mice survived for a maximum of only 6 days, the survival rate of micafungin-treated mice (0.1 mg kg(-1)) increased to 20%, while the survival rate of mice treated with a combination of micafungin (0.1 mg kg(-1)) and KB425796-C (32 mg kg(-1)) increased to 100% during the 31-day post-infection period. Our findings suggest that KB425796-C is a good candidate for the treatment of aspergillosis in combination with micafungin.
authors.affiliation: Drug Discovery Research, Astellas Pharma Inc., Tsukuba-shi, Ibaraki, Japan. hirohito.kai@astellas.com
authors.forename: Hirohito
authors.initials: H
authors.lastname: Kai
authors.forename: Midori
authors.initials: M
authors.lastname: Yamashita
authors.forename: Ikuko
authors.initials: I
authors.lastname: Nakamura
authors.forename: Koji
authors.initials: K
authors.lastname: Yoshikawa
authors.forename: Kumiko
authors.initials: K
authors.lastname: Nitta
authors.forename: Masato
authors.initials: M
authors.lastname: Watanabe
authors.forename: Noriaki
authors.initials: N
authors.lastname: Inamura
authors.forename: Akihiko
authors.initials: A
authors.lastname: Fujie
mesh_terms: D000818:Animals; D000935:Antifungal Agents / Q000008:administration & dosage / Q000302:isolation & purification / Q000494:pharmacology*; D001228:Aspergillosis / Q000188:drug therapy*; D001232:Aspergillus fumigatus / Q000187:drug effects*; D047630:Depsipeptides / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D004195:Disease Models, Animal; D025141:Drug Resistance, Fungal; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D054714:Echinocandins / Q000008:administration & dosage / Q000494:pharmacology*; D005260:Female; D007274:Injections, Intraperitoneal; D055666:Lipopeptides / Q000008:administration & dosage / Q000494:pharmacology*; D000077551:Micafungin; D051379:Mice; D008811:Mice, Inbred DBA; D008813:Mice, Inbred ICR; D056507:Paenibacillus / Q000378:metabolism; D018805:Sepsis / Q000188:drug therapy / Q000382:microbiology; D015996:Survival Rate; D014250:Trichosporon / Q000187:drug effects; D060586:Trichosporonosis / Q000188:drug therapy
chemical_list: D000935:Antifungal Agents; D047630:Depsipeptides; D054714:Echinocandins; C584029:KB425796-C; D055666:Lipopeptides; D000077551:Micafungin