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.

Antimicrobial Peptides: a New Frontier in Antifungal Therapy

“…Its mechanism of action is related to its structure, which resembles ferrichrome, an iron-chelating siderophore, and results in arrest of hyphal elongation. In a model of invasive pulmonary aspergillosis, immunocompromised mice treated with this compound survived longer and had lower lung fungal burdens than control animals ( 251 , 252 ). It was also efficacious against invasive candidiasis in neutropenic mice caused by drug-resistant C. glabrata ( 253 ).…”

Carrier-Mediated Drug Uptake in Fungal Pathogens

“…Its structure is similar to that of ferrichrome, a siderophore with high specificity for iron. VL-2397 was shown to have a strong antifungal activity against Aspergillus species, and also against other fungal species including Candida glabrata and Cryptococcus neoformans [ 36 ]. This drug was also demonstrated to be effective against azole resistant strains of Aspergillus fumigatus and Aspergillus terreus , and to have a faster, and more potent fungicidal effect in Aspergillus fumigatus germinated conidia and a stronger inhibition of hyphal elongation, than other antifungal agents like amphotericin B or azole drugs, such as posaconazole and voriconazole [ 36 ].…”

“…VL-2397 was shown to have a strong antifungal activity against Aspergillus species, and also against other fungal species including Candida glabrata and Cryptococcus neoformans [ 36 ]. This drug was also demonstrated to be effective against azole resistant strains of Aspergillus fumigatus and Aspergillus terreus , and to have a faster, and more potent fungicidal effect in Aspergillus fumigatus germinated conidia and a stronger inhibition of hyphal elongation, than other antifungal agents like amphotericin B or azole drugs, such as posaconazole and voriconazole [ 36 ]. In Aspergillus fumigatus , VL-2397 uptake was shown to be catalyzed by an importer for ferrichrome-type siderophores, Sit1, whose inactivation results in resistance to VL-2397 [ 37 ].…”

A Decade of Antifungal Leads from Natural Products: 2010–2019

“…The siderophore hexapeptide ASP2397 (96) was discovered as an aluminum chelate with exceptional potency against A. fumigatus, with an MIC of 0.2 µg/mL and efficacy at 3.2 mg/kg in a mouse in vivo model [79]. The metal-free form AS2488059 (97) as well as the congener AS2524371 (98) were also isolated, and the target was identified as a fungal siderophore transporter [80,81]. The compound was out-licensed to Vical and renamed VL-2397, reaching Phase II clinical trials that were recently discontinued.…”