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

• Published in: Antimicrobial agents and chemotherapy Vol. 63; no. 10
• Main Authors: Nakamura, Ikuko, Ohsumi, Keisuke, Takeda, Shinobu, Katsumata, Kiyomitsu, Matsumoto, Satoru, Akamatsu, Souichiro, Mitori, Hikaru, Nakai, Toru
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.10.2019
• Subjects: Antifungal Agents; Aspergillus; Aspergillus fumigatus; Coordination Complexes; Fungal Proteins; Peptides, Cyclic; Pharmacology; antifungal agent; fungicidal; aspergillosis; siderophore
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02689-18

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 (including azole-sensitive and azole-resistant isolates), , and at an MIC range of 1 to 4 μg/ml in human serum. Time-kill curve experiments showed that ASP2397 reduced germinated conidia of by more than 1 log CFU within 6 h. In addition, ASP2397 inhibited hyphal elongation from germinated conidia of , , and 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 log 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 with low susceptibility to ASP2397. The mutant had a point mutation in the siderophore transporter gene , which is absent in mammalian cells. These findings suggest that ASP2397 may improve clinical treatment options for IPA.