2025/07/17 by Bram Spruijtenburg, Theun de Groot, Eelco F. J. Meijer · 1 voice
Agricultural and Biological Sciences · Medicine · #Antifungal resistance and susceptibility #Fungal Infections and Studies #Plant-Microbe Interactions and Immunity
paper · pdf · doi:10.1093/jac/dkaf240
openalex publication_date 2025/07/17 · openalex created_date 2025/07/18 · openalex updated_date 2026/07/28
Candida auris (also known as Candidozyma auris) causes large and persistent outbreaks in healthcare settings and is associated with a high mortality rate in patients with invasive infections. Six genetically distinct clades have been reported that differ in their genetic background and vary in their virulence, antifungal resistance and capacity to cause an outbreak.1,2 Treatment options are limited owing to few approved antifungals, especially as resistance development during treatment has been reported for multiple drug classes, including echinocandins, the first-line therapy for systemic C. auris infections1. With resistance rates steadily increasing, there is an urgent need to identify novel drugs for future patient care. Triterpenoids comprise a new antifungal class that inhibit 1,3-β-glucan biosynthesis, a similar target to that of echinocandins.3 However, binding site profiles are different between the classes and while echinocandins are given IV, triterpenoids can be taken orally and demonstrate better tissue distribution. The first-in-class triterpenoid, ibrexafungerp (former SCY-078), was shown to inhibit the growth of different yeasts including several echinocandin-resistant isolates. Currently, a second-generation triterpenoid SCY-247 is under development with further enhanced tissue penetration. Ibrexafungerp and SCY-247 have demonstrated potent in vitro activity against a limited number of C. auris isolates, albeit with unknown information on genetic background or mutations in FKS1, encoding 1,3-β-glucan synthase.4 Therefore, we evaluated the in vitro activity of the second-generation triterpenoid SCY-247 against a genetically diverse collection of C. auris isolates, including FKS1 mutants. Sixty-five C. auris isolates from 14 countries, spanning clades I to V as determined with short tandem repeat (STR) genotyping, were included. In vitro antifungal susceptibility testing (AFST) against nine antifungals was conducted according to EUCAST E.Def v7.4 guidelines. SCY-247 powder was dissolved in DMSO (VWR, Amsterdam, The Netherlands) to a stock concentration of 3200 mg/L. Tested drug concentrations ranged from 0.002 to 16 mg/L. MICs were read with a spectrometer at 530 nm after 24 h of incubation. FKS1 hotspots 1, 2 and 3 were analysed for mutations using WGS or Sanger sequencing as previously described.5,6 Genomic data were made available under NCBI Genbank accession numbers PQ882627–PQ882695 and SRA PRJNA982799. The 65 C. auris isolates from clades I–V demonstrated highly variable in vitro MICs of azoles with following ranges (in mg/L): 2 to ≥ 64 (fluconazole), 0.008–8 (voriconazole), 0.008–0.25 (itraconazole), 0.008–0.25 (posaconazole) and 0.008–1 (isavuconazole). The amphotericin B range was narrower, with MICs of 0.25–1 mg/L (Table 1, available as Supplementary data at JAC Online). MICs of micafungin and anidulafungin varied highly, with ranges of 0.016 to ≥ 8 mg/L and 0.016 to ≥ 8 mg/L, respectively (Figure 1a). The FKS1 mutations S639T/Y/P/F, M690 V and Δ635F coincided with elevated MICs (MIC50 of 8 mg/L for both drugs) compared with WT isolates (MIC50 of 0.03 mg/L for both drugs). SCY-247 also demonstrated robust in vitro activity against all five clades, with a MIC range of 0.031–4 mg/L, showing an MIC50 of 0.125 mg/L for the WT isolates and 1 mg/L for the FKS1 mutants (Figure 1b). The 8-fold difference of MIC50 between WT and mutant isolates for SCY-247 was lower than the 256-fold difference observed with both micafungin and anidulafungin. Comparing individual FKS1 mutants, we found that for FKS1Δ635F the SCY-247 MIC was 4 mg/L and for both echinocandins the MIC was ≥8 mg/L. Except for a single S639Y isolate, which showed low MICs (0.25 mg/L) of all drugs, the other mutant isolates (with FKS1S639T/Y/F/P and FKS1M690V) demonstrated lower MICs of SCY-247 (0.25–2 mg/L) compared with the echinocandins (2 to ≥ 8 mg/L). In vitro antifungal susceptibility testing of Candida auris against echinocandins and SCY-247. MICs against echinocandins and SCY-247 were determined for all C. auris isolates (n=65) according to EUCAST E.Def v7.4 guidelines and plotted in mg/L between echinocandins (a) and the echinocandin micafungin and SCY-247 (b). Different dot colours refer to the different C. auris clades, symbols to different FKS1 mutations and red background to non-WT MIC values. MIC50, MIC at which growth was inhibited in 50% of isolates; AFG, anidulafungin; MFG, micafungin; WT, FKS1 wild-type isolates; Mut, FKS1 mutant isolates. We demonstrated that the SCY-247 MIC50 differed 8-fold between WT and FKS1 mutant isolates, while this was 256-fold for the echinocandins. This indicates that these FKS1 mutations strongly reduce the susceptibility of C. auris to echinocandins, as is also shown in vivo, but have a modest impact on the efficacy of SCY-247, at least in vitro.6 This is likely due to SCY-247’s different binding site profile. While the SCY-247 MICs for virtually all FKS1 mutants were lower compared with echinocandins, this higher in vitro activity does not necessarily reflect higher efficacy in vivo, although they are from the same pharmacological class.7 Furthermore, in vitro SCY-247 showed potent activity across all tested clades with WT FKS1, while azole antifungal resistance rates highly varied between isolates. Also, echinocandins only reach the urinary tract in subtherapeutic concentrations, which, as a consequence, is known as a sanctuary site facilitating resistance development for this class.5 Importantly, SCY-247 was designed to achieve higher tissue and potentially urinary concentrations (to be confirmed in clinical investigations), aiming to introduce a novel systemic treatment option with lower potential for resistance development.4 Thus, with a Phase I trial currently underway, this new antifungal could be a promising option to treat patients infected by susceptible and even echinocandin-resistant C. auris isolates. Nonetheless, pre-clinical in vivo studies are first needed to explore potential clinical usage. In addition, the efficacy against clade VI isolates and the effect of FKS1 mutations on SCY-247 in isolates other than clade I also remains to be assessed. Altogether, the novel antifungal SCY-247 demonstrated potent in vitro activity against genetically diverse C. auris isolates, including several FKS1 mutants with elevated echinocandin MICs. We would like to thank Dirk Faro for technical assistance. This work was supported by SCYNEXIS, Inc. and the Canisius-Wilhelmina Hospital (grant CWZ001421). E.F.J.M. received research grants form Mundipharma, is on the scientific advisory board for Pfizer and has received speaker fees from Gilead Sciences. All other authors declare no conflicts of interest. Table S1 and Figure S1 are available as Supplementary data at JAC Online.