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

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.

• Authors: Ikuko Nakamura, Keisuke Ohsumi, Shinobu Takeda, Kiyomitsu Katsumata, Satoru Matsumoto, Souichiro Akamatsu, Hikaru Mitori, Toru Nakai
• Journal: Antimicrobial agents and chemotherapy (Antimicrob Agents Chemother) Vol. 63 Issue 10 (10 2019) ISSN: 1098-6596 [Electronic] United States
• PMID: 31405853 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 American Society for Microbiology.

Chemical References

• Antifungal Agents
• Coordination Complexes
• Fungal Proteins
• Peptides, Cyclic
• Siderophores
• VL-2397

Topics

• Antifungal Agents (pharmacology)
• Aspergillus (drug effects, metabolism)
• Aspergillus fumigatus (drug effects, metabolism)
• Coordination Complexes (pharmacology)
• Drug Resistance, Fungal (genetics)
• Fungal Proteins (genetics, metabolism)
• Humans
• Microbial Sensitivity Tests
• Peptides, Cyclic (pharmacology)
• Siderophores (chemistry)