mk-3118 and Candidiasis

Invasive fungal infections represent an expanding threat to public health. The recent emergence of Candida auris, which is often resistant to existing antifungal agents and is associated with a high mortality rate, underscores the urgent need for novel drug development strategies. Areas covered: In this paper, we examine both challenges and opportunities associated with antifungal drug development and explore potential avenues to accelerate the development pipeline, including data sharing, surrogate endpoints, and the role of historical controls in clinical trials. Expert commentary: We review important lessons learned from the study of other rare diseases, including mitochondrial storage diseases and certain forms of cancer that may inform strategies to develop new antifungal agents while highlighting promising new compounds such as SCY-078 for the treatment of invasive fungal infections.

Topics: Antifungal Agents; Biomarkers; Candida; Candidiasis; Clinical Trials as Topic; Drug Design; Drug Resistance, Fungal; Echinocandins; Glycosides; Humans; Invasive Fungal Infections; Microbial Sensitivity Tests; Nitriles; Pyridines; Triazoles; Triterpenes

We previously reported medicinal chemistry efforts that identified MK-5204, an orally efficacious β-1,3-glucan synthesis inhibitor derived from the natural product enfumafungin. Further extensive optimization of the C2 triazole substituent identified 4-pyridyl as the preferred replacement for the carboxamide of MK-5204, leading to improvements in antifungal activity in the presence of serum, and increased oral exposure. Reoptimizing the aminoether at C3 in the presence of this newly discovered C2 substituent, confirmed that the (R) t-butyl, methyl aminoether of MK-5204 provided the best balance of these two key parameters, culminating in the discovery of ibrexafungerp, which is currently in phase III clinical trials. Ibrexafungerp displayed significantly improved oral efficacy in murine infection models, making it a superior candidate for clinical development as an oral treatment for Candida and Aspergillus infections.

Topics: Administration, Oral; Animals; Antifungal Agents; Aspergillosis; Aspergillus; beta-Glucans; Candida albicans; Candidiasis; Disease Models, Animal; Glycosides; Half-Life; Mice; Structure-Activity Relationship; Triterpenes

Emergence of azole resistance may contribute to recurrences of vulvovaginal candidiasis. Thus, new drugs are needed to improve the therapeutic options. We studied the in vitro activity of ibrexafungerp and comparators against Candida albicans isolates from vaginal samples and blood cultures. Furthermore, isolates were genotyped to study compartmentalization of genotypes and the relationship between genotype and antifungal susceptibility.. Candida albicans unique patient isolates (n = 144) from patients with clinical suspicion of vulvovaginal candidiasis (n = 72 isolates) and from patients with candidaemia (n = 72) were studied. Antifungal susceptibility to amphotericin B, fluconazole, voriconazole, posaconazole, isavuconazole, clotrimazole, miconazole, micafungin, anidulafungin and ibrexafungerp was tested (EUCAST 7.3.2). Mutations in the erg11 gene were analysed and isolates genotyped.. Ibrexafungerp showed high activity (MICs from 0.03 mg/L to 0.25 mg/L) against the isolates, including those with reduced azole susceptibility, and regardless of their clinical source. Fluconazole resistance rate was 7% (n = 5/72) and 1.4% (n = 1/72) in vaginal and blood isolates, respectively. Some amino acid substitutions in the Erg11 protein were observed exclusively in phenotypically fluconazole non-wild type. Population structure analysis suggested two genotype populations, one mostly involving isolates from blood samples (66.3%) and the mostly from vaginal samples (69.8%). The latter group hosted all fluconazole non-wild-type isolates.. Ibrexafungerp shows good in vitro activity against Candida albicans from vaginal samples including phenotypically fluconazole non-wild-type isolates. Furthermore, we found a certain population structure where some genotypes show reduced susceptibility to fluconazole.

Topics: Antifungal Agents; Candida albicans; Candidemia; Candidiasis; Drug Resistance, Fungal; Female; Glycosides; Humans; Microbial Sensitivity Tests; Triterpenes

Ibrexafungerp (IBX), formerly SCY-078, is a novel, oral and intravenous, semisynthetic triterpenoid glucan synthase inhibitor in clinical development for treating multiple fungal infections, including invasive candidiasis. Intra-abdominal candidiasis (IAC) is one of the most common types of invasive candidiasis associated with high mortality largely due to poor drug exposure in infected lesions. To better understand the potential of IBX to treat such infections, we investigated its penetration at the site of infection. Using matrix-assisted laser desorption ionization-mass spectrometry imaging (MALDI-MSI) and laser capture microdissection (LCM)-directed high-pressure liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS), we investigated tissue distribution and lesion-specific drug exposure of IBX in a clinically relevant IAC mouse model. After a single-dose treatment, IBX quickly distributed into tissues and efficiently accumulated within lesions. Drug concentrations of IBX within the liver abscesses were almost 100-fold higher than the serum concentration. In addition, drug penetration after repeated treatment of IBX was compared with micafungin. IBX exhibited robust and long-lasting lesion penetration after repeated treatment. These data indicate that IBX penetrates into intra-abdominal abscesses highly efficiently and holds promise as a potential therapeutic option for IAC patients.

Topics: Animals; Antifungal Agents; Candidiasis; Chromatography, High Pressure Liquid; Disease Models, Animal; Female; Glycosides; Laser Capture Microdissection; Mice; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Tandem Mass Spectrometry; Triterpenes

Topics: Antifungal Agents; Candida; Candidiasis; Cross Infection; Disease Outbreaks; Drug Resistance, Multiple, Fungal; Glucosyltransferases; Glycosides; Humans; Microbial Sensitivity Tests; New York; Triterpenes

Topics: Antifungal Agents; Candida; Candidiasis; Drug Resistance, Fungal; Glycosides; Humans; Microbial Sensitivity Tests; Triterpenes

SCY-078 (formerly MK-3118) is a novel orally active inhibitor of fungal β-(1,3)-glucan synthase (GS). SCY-078 is a derivative of enfumafungin and is structurally distinct from the echinocandin class of antifungal agents. We evaluated the

Topics: Administration, Oral; Antifungal Agents; Candida; Candida glabrata; Candidiasis; Drug Resistance, Fungal; Echinocandins; Glucosyltransferases; Glycosides; Microbial Sensitivity Tests; Mutation; Triterpenes

SCY-078 is an orally active antifungal whose target is the β-(1,3)-d-glucan synthase (GS). We evaluated the spontaneous emergence of SCY-078-resistant

Topics: Antifungal Agents; Candida glabrata; Candidiasis; Drug Resistance, Fungal; Echinocandins; Fungal Proteins; Glucosyltransferases; Glycosides; Humans; Microbial Sensitivity Tests; Mutation; Triterpenes

We studied the antifungal activity of SCY-078 (an orally bioavailable 1,3-β -d- glucan synthesis inhibitor), micafungin and fluconazole against the planktonic and sessile forms of 178 Candida and non- Candida isolates causing fungaemia in patients recently admitted to a large European hospital.. The in vitro activity of SCY-078, micafungin and fluconazole against the planktonic form of the isolates was assessed using EUCAST EDef 7.3 and CLSI M27-A3. Antibiofilm activity was assessed using the XTT reduction assay.. SCY-078 and micafungin showed potent in vitro activity against Candida and non- Candida isolates. The in vitro activity of both drugs was similar, but SYC-078 displayed significantly lower MIC values than micafungin against Candida parapsilosis and non- Candida isolates, whereas micafungin displayed significantly lower MIC values for the remaining species ( P  <0.001). In contrast, SCY-078 and micafungin showed essentially the same activity against the biofilms with the exception of Candida glabrata , in which the micafungin sessile MIC values were significantly lower ( P  <0.001). These observations were confirmed by assessing biofilm structure by scanning electron microscopy after antifungal treatment.. Our study showed that the high in vitro activity of SCY-078 against invasive Candida isolates in both sessile and planktonic forms is comparable to that of micafungin.

Topics: Antifungal Agents; Biofilms; Candida; Candida albicans; Candida glabrata; Candidiasis; Candidiasis, Invasive; Echinocandins; Glucosyltransferases; Glycosides; Humans; Lipopeptides; Micafungin; Microbial Sensitivity Tests; Triterpenes

To evaluate the activity of the orally bioavailable enfumafungin derivative MK-3118 and comparator antifungal agents tested against a collection of 113 clinical isolates of Candida spp. using CLSI and EUCAST broth microdilution (BMD) methods.. Candida spp. isolates (n=113) were tested by CLSI and EUCAST methods. The collection contained 29 Candida albicans, 29 Candida glabrata, 21 Candida tropicalis, 15 Candida parapsilosis and 19 Candida krusei, including azole- and echinocandin-resistant isolates. CLSI and EUCAST MIC endpoints of 50% and 100% inhibition were determined using visual reading at 24 and 48 h of incubation and spectrophotometric reading at 24 h of incubation, respectively.. MK-3118 CLSI MIC results ranged from 0.06 to 16 mg/L depending on species, duration of incubation and endpoint criteria (EC) used. Comparison of CLSI and EUCAST following 24 h of incubation and either 50% or 100% inhibition revealed an essential agreement (EA; ± 2 doubling dilutions) of 99.1% using the 50% inhibition EC and 93.2% using the 100% inhibition EC. MK-3118 (24 h of incubation and 50% EC) was active against all the species tested and displayed similar potency to caspofungin (using CLSI BMD) against C. albicans (MIC90, 1 and 2 mg/L, respectively), C. tropicalis (1 and 1 mg/L, respectively), C. parapsilosis (0.5 and 0.5 mg/L, respectively) and C. krusei (2 and 1 mg/L, respectively), but was 8-fold more potent than caspofungin against C. glabrata strains (MIC90, 2 and 16 mg/L, respectively). MK-3118 was active against fluconazole-resistant strains as well as caspofungin-resistant strains with documented fks mutations.. MK-3118 was documented to have potent in vitro activity against Candida spp. when tested by both CLSI and EUCAST BMD methods, with the highest overall EA (99.1%) obtained when MK-3118 MIC results were read after 24 h of incubation using a partial inhibition EC (50%).

Topics: Antifungal Agents; Candida; Candidiasis; Glucosyltransferases; Glycosides; Humans; Microbial Sensitivity Tests; Time Factors; Triterpenes