ASP2397 Is a Novel Natural Compound That Exhibits Rapid and Potent Fungicidal Activity against <i>Aspergillus</i> 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 <i>Aspergillus fumigatus</i> (including azole-sensitive and azole-resistant isolates), <i>A. terreus</i>, and <i>A. flavus</i> at an MIC range of 1 to 4 μg/ml in human serum. Time-kill curve experiments showed that ASP2397 reduced germinated conidia of <i>A. fumigatus</i> by more than 1 log₁₀ CFU within 6 h. In addition, ASP2397 inhibited hyphal elongation from germinated conidia of <i>A. fumigatus</i>, <i>A. terreus</i>, and <i>A. flavus</i> 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 <i>A. fumigatus</i> with low susceptibility to ASP2397. The mutant had a point mutation in the siderophore transporter gene <i>sit1</i>, which is absent in mammalian cells. These findings suggest that ASP2397 may improve clinical treatment options for IPA.