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ASP2397 Is a Novel Natural Compound That Exhibits Rapid and Potent Fungicidal Activity against Aspergillus Species through a Specific Transporter.

Authors
  • Nakamura, Ikuko1
  • Ohsumi, Keisuke1
  • Takeda, Shinobu2
  • Katsumata, Kiyomitsu1
  • Matsumoto, Satoru1
  • Akamatsu, Souichiro1
  • Mitori, Hikaru1
  • Nakai, Toru1
  • 1 Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan. , (Japan)
  • 2 Drug Discovery Research, Astellas Pharma Inc., Ibaraki, Japan [email protected] , (Japan)
Type
Published Article
Journal
Antimicrobial Agents and Chemotherapy
Publisher
American Society for Microbiology
Publication Date
Oct 01, 2019
Volume
63
Issue
10
Identifiers
DOI: 10.1128/AAC.02689-18
PMID: 31405853
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Current therapies against invasive pulmonary aspergillosis (IPA) have a limited cure rate. Given that a delay in treatment initiation may be fatal, a new drug with rapid-onset and potent fungicidal activity is needed. The novel cyclic hexapeptide ASP2397 (currently known as VL-2397) exhibited antifungal activity against Aspergillus fumigatus (including azole-sensitive and azole-resistant isolates), A. terreus, and A. flavus at an MIC range of 1 to 4 μg/ml in human serum. Time-kill curve experiments showed that ASP2397 reduced germinated conidia of A. fumigatus by more than 1 log10 CFU within 6 h. In addition, ASP2397 inhibited hyphal elongation from germinated conidia of A. fumigatus, A. terreus, and A. flavus more rapidly than voriconazole. Under conditions of delayed treatment initiation in an IPA mouse model, ASP2397 had efficacy superior to that of posaconazole, with 100% survival and over 1 log10 CFU/g reduction in lung fungal burden. Histopathological investigation of lungs also showed that ASP2397 markedly suppressed disease progression. To clarify its mechanism of action, we generated a UV-induced mutant of A. fumigatus with low susceptibility to ASP2397. The mutant had a point mutation in the siderophore transporter gene sit1, which is absent in mammalian cells. These findings suggest that ASP2397 may improve clinical treatment options for IPA. Copyright © 2019 American Society for Microbiology.

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