Oral glucan synthase inhibitor SCY-078 is effective in an experimental murine model of invasive candidiasis caused by WT and echinocandin-resistant Candida glabrata

ABSTRACT Ibrexafungerp is a first-in-class glucan synthase inhibitor. In vitro activity was determined for 89 Candida glabrata isolates with molecularly identified FKS1 or FKS2 mutations conferring resistance to the echinocandins. All isolates were resistant to at least one echinocandin (i.e., anidulafungin, caspofungin, or micafungin) by broth microdilution. Results for ibrexafungerp were compared with those for each echinocandin. Ibrexafungerp had good activity against all echinocandin-resistant C. glabrata isolates.

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Development of Caspofungin Resistance following Prolonged Therapy for Invasive Candidiasis Secondary to Candida glabrata Infection

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00473-08 ◽

2008 ◽

Vol 52 (10) ◽

pp. 3783-3785 ◽

Cited By ~ 106

Author(s):

George R. Thompson ◽

Nathan P. Wiederhold ◽

Ana C. Vallor ◽

Nyria C. Villareal ◽

James S. Lewis ◽

...

Keyword(s):

Invasive Candidiasis ◽

Hot Spots ◽

Candida Glabrata ◽

Glucan Synthase ◽

Prolonged Therapy ◽

Echinocandin Resistance

ABSTRACT We report a case of Candida glabrata invasive candidiasis that developed reduced susceptibility to caspofungin during prolonged therapy. Pre- and posttreatment isolates were confirmed to be isogenic, and sequencing of hot spots known to confer echinocandin resistance revealed an F659V substitution within the FKS2 region of the glucan synthase complex.

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Activity of a Novel 1,3-Beta-D-Glucan Synthase Inhibitor, Ibrexafungerp (Formerly SCY-078), against Candida glabrata

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01510-19 ◽

2019 ◽

Vol 63 (12) ◽

Cited By ~ 5

Author(s):

M. Ghannoum ◽

L. Long ◽

N. Isham ◽

C. Hager ◽

R. Wilson ◽

...

Keyword(s):

Candida Glabrata ◽

Wild Type ◽

Glucan Synthase ◽

Content Type ◽

Clinical Strains ◽

Resistant Strains ◽

Oral Availability ◽

Synthase Inhibitor ◽

Time Kill ◽

Type Strains

ABSTRACT Ibrexafungerp (formerly SCY-078), a novel glucan synthase inhibitor with oral availability, was evaluated for activity against Candida glabrata. The susceptibility of clinical strains to ibrexafungerp was determined by microdilution and time-kill assays. The MIC range against wild-type strains was 1 to 2 μg/ml. Ibrexafungerp was also active against the majority of echinocandin-resistant strains. Time-kill studies showed 4- to 6-log-unit reductions in growth at 24 and 48 h with concentrations of 0.25 to 4 μg/ml.

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Pharmacodynamic Target Evaluation of a Novel Oral Glucan Synthase Inhibitor, SCY-078 (MK-3118), Using anIn VivoMurine Invasive Candidiasis Model

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.04445-14 ◽

2014 ◽

Vol 59 (2) ◽

pp. 1265-1272 ◽

Cited By ~ 47

Author(s):

Alexander J. Lepak ◽

Karen Marchillo ◽

David R. Andes

Keyword(s):

Invasive Candidiasis ◽

Target Identification ◽

Dose Range ◽

Time Curve ◽

Glucan Synthase ◽

Content Type ◽

First Line Therapy ◽

Drug Concentrations ◽

Synthase Inhibitor

ABSTRACTEchinocandins inhibit the synthesis of β-1,3-d-glucan inCandidaand are the first-line therapy in numerous clinical settings. Their use is limited by poor oral bioavailability, and they are available only as intravenous therapies. Derivatives of enfumafungin are novel orally bioavailable glucan synthase inhibitors. We performed anin vivopharmacodynamic (PD) evaluation with a novel enfumafungin derivative, SCY-078 (formerly MK-3118), in a well-established neutropenic murine model of invasive candidiasis againstC. albicans,C. glabrata, andC. parapsilosis. The SCY-078 MICs varied 8-fold. Oral doses of 3.125 to 200 mg/kg SCY-078 salt in sterile water produced peak levels of 0.04 to 2.66 μg/ml, elimination half-lives of 5.8 to 8.5 h, areas under the concentration-time curve from 0 to 24 h (AUC0–24 h) of 0.61 to 41.10 μg · h/ml, and AUC from 0 to infinity (AUC0—∞) values of 0.68 to 40.31 μg · h/ml. The pharmacokinetics (PK) were approximately linear over the dose range studied. Maximum response (Emax) and PK/PD target identification studies were performed with 4C. albicans, 4C. glabrata, and 3C. parapsilosisisolates. The PD index AUC/MIC was explored by using total (tAUC) and free (fAUC) drug concentrations. The maximum responses were 4.0, 4.0, and 4.3 log10CFU/kidney reductions forC. albicans,C. glabrata, andC. parapsilosis, respectively. The AUC/MIC was a robust predictor of efficacy (R2, 0.53 to 0.91). The 24-h PD targets were a static dose of 63.5 mg/kg, atAUC/MIC of 500, and anfAUC/MIC of 1.0 forC. albicans; a static dose of 58.4 mg/kg, atAUC/MIC of 315, and anfAUC/MIC of 0.63 forC. glabrata; and a static dose of 84.4 mg/kg, atAUC/MIC of 198, and anfAUC/MIC of 0.40 forC. parapsilosis. The meanfAUC/MIC values associated with a 1-log kill endpoint against these species were 1.42, 1.26, and 0.91 forC. albicans,C. glabrata, andC. parapsilosis, respectively. The static and 1-log kill endpoints were measured relative to the burden at the start of therapy. The static and 1-log kill doses, as well as the total and free drug AUC/MIC PD targets, were not statistically different between species but were numerically lower than those observed for echinocandins. SCY-078 is a promising novel oral glucan synthase inhibitor againstCandidaspecies, and further investigation is warranted.

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Protective Activity of S-PT84, a Heat-killed Preparation of Lactobacillus pentosus, against Oral and Gastric Candidiasis in an Experimental Murine Model

Medical Mycology Journal ◽

10.3314/mmj.55.j123 ◽

2014 ◽

Vol 55 (3) ◽

pp. J123-J129 ◽

Cited By ~ 6

Author(s):

Kazumi Hayama ◽

Sanae Ishijima ◽

Yoshiko Ono ◽

Takayuki Izumo ◽

Masayuki Ida ◽

...

Keyword(s):

Murine Model ◽

Protective Activity ◽

Lactobacillus Pentosus ◽

Experimental Murine Model

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Discovery of a Novel Class of Orally Active Antifungal β-1,3-d-Glucan Synthase Inhibitors

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00432-11 ◽

2011 ◽

Vol 55 (11) ◽

pp. 5099-5106 ◽

Cited By ~ 38

Author(s):

Scott S. Walker ◽

Yiming Xu ◽

Ilias Triantafyllou ◽

Michelle F. Waldman ◽

Cara Mendrick ◽

...

Keyword(s):

Saccharomyces Cerevisiae ◽

Candida Glabrata ◽

Pharmacokinetic Data ◽

Morphological Response ◽

Glucan Synthase ◽

Content Type ◽

Safety Issues ◽

Spontaneous Mutants ◽

Orally Active

ABSTRACTThe echinocandins are a class of semisynthetic natural products that target β-1,3-glucan synthase (GS). Their proven clinical efficacy combined with minimal safety issues has made the echinocandins an important asset in the management of fungal infection in a variety of patient populations. However, the echinocandins are delivered only parenterally. A screen for antifungal bioactivities combined with mechanism-of-action studies identified a class of piperazinyl-pyridazinones that target GS. The compounds exhibitedin vitroactivity comparable, and in some cases superior, to that of the echinocandins. The compounds inhibit GSin vitro, and there was a strong correlation between enzyme inhibition andin vitroantifungal activity. In addition, like the echinocandins, the compounds caused a leakage of cytoplasmic contents from yeast and produced a morphological response in molds characteristic of GS inhibitors. Spontaneous mutants ofSaccharomyces cerevisiaewith reduced susceptibility to the piperazinyl-pyridazinones had substitutions inFKS1. The sites of these substitutions were distinct from those conferring resistance to echinocandins; likewise, echinocandin-resistant isolates remained susceptible to the test compounds. Finally, we present efficacy and pharmacokinetic data on an example of the piperazinyl-pyridazinone compounds that demonstrated efficacy in a murine model ofCandida glabratainfection.

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Quantitation of Candida albicans Ergosterol Content Improves the Correlation between In Vitro Antifungal Susceptibility Test Results and In Vivo Outcome after Fluconazole Treatment in a Murine Model of Invasive Candidiasis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.44.8.2081-2085.2000 ◽

2000 ◽

Vol 44 (8) ◽

pp. 2081-2085 ◽

Cited By ~ 90

Author(s):

Beth A. Arthington-Skaggs ◽

David W. Warnock ◽

Christine J. Morrison

Keyword(s):

Murine Model ◽

Invasive Candidiasis ◽

Clinical Laboratory ◽

Antifungal Susceptibility ◽

Resistant Isolate ◽

National Committee ◽

Ergosterol Content ◽

In Vitro Antifungal Susceptibility

ABSTRACT MIC end point determination for the most commonly prescribed azole antifungal drug, fluconazole, can be complicated by “trailing” growth of the organism during susceptibility testing by the National Committee for Clinical Laboratory Standards approved M27-A broth macrodilution method and its modified broth microdilution format. To address this problem, we previously developed the sterol quantitation method (SQM) for in vitro determination of fluconazole susceptibility, which measures cellular ergosterol content rather than growth inhibition after exposure to fluconazole. To determine if SQM MICs of fluconazole correlated better with in vivo outcome than M27-A MICs, we used a murine model of invasive candidiasis and analyzed the capacity of fluconazole to treat infections caused by C. albicansisolates which were trailers (M27-A MICs at 24 and 48 h, ≤1.0 and ≥64 μg/ml, respectively; SQM MIC, ≤1.0 μg/ml), as well as those which were fluconazole sensitive (M27-A and SQM MIC, ≤1.0 μg/ml) and fluconazole resistant (M27-A MIC, ≥64 μg/ml; SQM MIC, 54 μg/ml). Compared with the untreated controls, fluconazole therapy increased the survival of mice infected with a sensitive isolate and both trailing isolates but did not increase the survival of mice infected with a resistant isolate. These results indicate that the SQM is more predictive of in vivo outcome than the M27-A method for isolates that give unclear MIC end points due to trailing growth in fluconazole.

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