scholarly journals Ibrexafungerp, a Novel Oral Triterpenoid Antifungal in Development: Overview of Antifungal Activity Against Candida glabrata

2021 ◽  
Vol 11 ◽  
Author(s):  
Ahmed Gamal ◽  
Sherman Chu ◽  
Thomas S. McCormick ◽  
Katyna Borroto-Esoda ◽  
David Angulo ◽  
...  
Keyword(s):  
Candida Glabrata ◽  
Systemic Disease ◽  
Wild Type ◽  
First Line ◽  
Life Threatening ◽  
Oral Availability ◽  
Synthase Inhibitor ◽  
Preclinical And Clinical Studies ◽  
Systemic Infections

Systemic infections caused by Candida species are an important cause of morbidity and mortality among immunocompromised and non-immunocompromised patients. In particular, Candida glabrata is an emerging species within the Candida family that causes infections ranging from superficial to life-threatening systemic disease. Echinocandins and azoles are typically the first-line therapies used to treat infections caused by C. glabrata, however, there is an increasing prevalence of resistance to these antifungal agents in patients. Thus, a need exists for novel therapies that demonstrate high efficacy against C. glabrata. Ibrexafungerp is a first-in-class glucan synthase inhibitor with oral availability developed to address this increasing antifungal resistance. Ibrexafungerp demonstrates broad in vitro activity against wild-type, azole-resistant, and echinocandin-resistant C. glabrata species. Furthermore, ibrexafungerp has shown efficacy in low pH environments, which suggests its potential effectiveness in treating vulvovaginal candidiasis. Additional preclinical and clinical studies are needed to further examine the mechanism(s) of ibrexafungerp, including acting as a promising new agent for treating C. glabrata infections.

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

2019 ◽  
Vol 63 (12) ◽  
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.

scholarly journals In Vitro Activity of Ibrexafungerp, a Novel Glucan Synthase Inhibitor against Candida glabrata Isolates with FKS Mutations

2019 ◽  
Vol 63 (11) ◽  
Author(s):  
Natalie S. Nunnally ◽  
Kizee A. Etienne ◽  
David Angulo ◽  
Shawn R. Lockhart ◽  
Elizabeth L. Berkow
Keyword(s):  
Candida Glabrata ◽  
Vitro Activity ◽  
Good Activity ◽  
In Vitro Activity ◽  
Broth Microdilution ◽  
Glucan Synthase ◽  
Content Type ◽  
Synthase Inhibitor

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.

scholarly journals Antifungal Activity of SCY-078 and Standard Antifungal Agents against 178 Clinical Isolates of Resistant and Susceptible Candida Species

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Wiley A. Schell ◽  
A. M. Jones ◽  
Katyna Borroto-Esoda ◽  
Barbara D. Alexander
Keyword(s):  
Candida Glabrata ◽  
Antifungal Agents ◽  
Candida Parapsilosis ◽  
Candida Krusei ◽  
Wild Type ◽  
Content Type ◽  
Clinical Resistance ◽  
Excellent Activity ◽  
Candida Lusitaniae

ABSTRACT SCY-078 in vitro activity was determined for 178 isolates of resistant or susceptible Candida albicans, Candida dubliniensis, Candida glabrata, Candida krusei, Candida lusitaniae, and Candida parapsilosis, including 44 Candida isolates with known genotypic (FKS1 or FKS2 mutations), phenotypic, or clinical resistance to echinocandins. Results were compared to those for anidulafungin, caspofungin, micafungin, fluconazole, and voriconazole. SCY-078 was shown to have excellent activity against both wild-type isolates and echinocandin- and azole-resistant isolates of Candida species.

scholarly journals Posaconazole against Candida glabrata Isolates with Various Susceptibilities to Fluconazole

2008 ◽  
Vol 52 (6) ◽  
pp. 1929-1933 ◽  
Author(s):  
Elisabetta Spreghini ◽  
Carmelo Massimo Maida ◽  
Serena Tomassetti ◽  
Fiorenza Orlando ◽  
Daniele Giannini ◽  
...  
Keyword(s):  
Experimental Model ◽  
Candida Glabrata ◽  
Therapeutic Option ◽  
Resistant Isolate ◽  
Dependent Manner ◽  
Fungal Burden ◽  
Systemic Infections ◽  
Time Kill ◽  
Dose Dependent

ABSTRACT We investigated the in vitro activities of posaconazole (POS), fluconazole (FLC), amphotericin B (AMB), and caspofungin (CAS) against four clinical isolates of Candida glabrata with various susceptibilities to FLC (FLC MICs ranging from 1.0 to >64 μg/ml). POS MICs ranged from ≤0.03 to 0.5 μg/ml; AMB MICs ranged from 0.25 to 2.0 μg/ml, while CAS MICs ranged from 0.03 to 0.25 μg/ml. When FLC MICs increased, so did POS MICs, although we did not observe any isolate with a POS MIC greater than 0.5 μg/ml. Time-kill experiments showed that POS, FLC, and CAS were fungistatic against all isolates, while AMB at eight times the MIC was fungicidal against three out of four isolates of C. glabrata tested. Then, we investigated the activity of POS in an experimental model of disseminated candidiasis using three different isolates of C. glabrata: one susceptible to FLC (S; FLC MICs ranging from 1.0 to 4.0 μg/ml; POS MIC of ≤0.03 μg/ml), one susceptible in a dose-dependent manner (SDD; FLC MICs ranging from 32 to 64 μg/ml; POS MICs ranging from 0.125 to 0.25 μg/ml), and another one resistant to FLC (R; FLC MIC of >64 μg/ml; POS MIC of 0.5 μg/ml). FLC significantly reduced the kidney burden of mice infected with the S strain (P = 0.0070) but not of those infected with the S-DD and R strains. POS was significantly effective against all three isolates at reducing the kidney fungal burden with respect to the controls (P ranging from 0.0003 to 0.029). In conclusion, our data suggest that POS may be a useful option in the management of systemic infections caused by C. glabrata. Additionally, the new triazole may be a therapeutic option in those cases where an FLC-resistant isolate is found to retain a relatively low POS MIC.

scholarly journals Overview of medically important antifungal azole derivatives.

1988 ◽  
Vol 1 (2) ◽  
pp. 187-217 ◽  
Author(s):  
R A Fromtling
Keyword(s):  
Adverse Reactions ◽  
Fungal Infections ◽  
Chemotherapeutic Agents ◽  
Skin Infections ◽  
Life Threatening ◽  
Major Chemical ◽  
Systemic Infections ◽  
Selection Of

Fungal infections are a major burden to the health and welfare of modern humans. They range from simply cosmetic, non-life-threatening skin infections to severe, systemic infections that may lead to significant debilitation or death. The selection of chemotherapeutic agents useful for the treatment of fungal infections is small. In this overview, a major chemical group with antifungal activity, the azole derivatives, is examined. Included are historical and state of the art information on the in vitro activity, experimental in vivo activity, mode of action, pharmacokinetics, clinical studies, and uses and adverse reactions of imidazoles currently marketed (clotrimazole, miconazole, econazole, ketoconazole, bifonazole, butoconazole, croconazole, fenticonazole, isoconazole, oxiconazole, sulconazole, and tioconazole) and under development (aliconazole and omoconazole), as well as triazoles currently marketed (terconazole) and under development (fluconazole, itraconazole, vibunazole, alteconazole, and ICI 195,739).

scholarly journals Phage Therapy of Local and Systemic Disease Caused by Vibrio vulnificus in Iron-Dextran-Treated Mice

2002 ◽  
Vol 70 (11) ◽  
pp. 6251-6262 ◽  
Author(s):  
Karen E. Cerveny ◽  
Angelo DePaola ◽  
Donna H. Duckworth ◽  
Paul A. Gulig
Keyword(s):  
Phage Therapy ◽  
Vibrio Vulnificus ◽  
Therapeutic Potential ◽  
Systemic Disease ◽  
Lethal Dose ◽  
Rapid Progression ◽  
Iron Dextran ◽  
Histopathologic Analysis ◽  
Systemic Infections

ABSTRACT Vibrio vulnificus is a gram-negative bacterium that contaminates filter-feeding shellfish such as oysters. After ingestion of contaminated oysters, predisposed people may experience highly lethal septicemia. Contamination of wounds with the bacteria can result in devastating necrotizing fasciitis, which can progress to septicemia. The extremely rapid progression of these diseases can render antibiotic treatment ineffective, and death is a frequent outcome. In this study, we examined the potential use of bacteriophages as therapeutic agents against V. vulnificus in an iron-dextran-treated mouse model of V. vulnificus infection. Mice were injected subcutaneously with 10 times the lethal dose of V. vulnificus and injected intravenously, either simultaneously or at various times after infection, with phages. Treatment of mice with phages could prevent death; systemic disease, as measured by CFU per gram of liver and body temperature; and local disease, as measured by CFU per gram of lesion material and histopathologic analysis. Two different phages were effective against three different V. vulnificus strains with various degrees of virulence, while a third phage that required the presence of seawater to lyse bacteria in vitro was ineffective at treating mice. Optimum protection required that the phages be administered within 3 h of bacterial inoculation at doses as high as 108 PFU. One of the protective phages had a half-life in blood of over 2 h. These results demonstrate that bacteriophages have therapeutic potential for both localized and systemic infections caused by V. vulnificus in animals. This model should be useful in answering basic questions regarding phage therapy.

Impact of calmodulin inhibition by fluphenazine on susceptibility, biofilm formation and pathogenicity of caspofungin-resistant Candida glabrata

2020 ◽  
Vol 75 (5) ◽  
pp. 1187-1193 ◽  
Author(s):  
Andrés Ceballos Garzon ◽  
Daniela Amado ◽  
Estelle Robert ◽  
Claudia M Parra Giraldo ◽  
Patrice Le Pape
Keyword(s):  
Biofilm Formation ◽  
Candida Glabrata ◽  
Galleria Mellonella ◽  
Larval Survival ◽  
Clinical Isolates ◽  
Dilution Method ◽  
Life Threatening ◽  
Polyurethane Catheter ◽  
The Impact

Abstract Background In recent decades, Candida glabrata has emerged as a frequent cause of life-threatening fungal infection. In C. glabrata, echinocandin resistance is associated with mutations in FKS1/FKS2 (β-1,3-glucan synthase). The calmodulin/calcineurin pathway is implicated in response to antifungal stress and calcineurin gene disruption specifically reverses Fks2-mediated resistance of clinical isolates. Objectives We evaluated the impact of calmodulin inhibition by fluphenazine in two caspofungin-resistant C. glabrata isolates. Methods C. glabrata isolates were identified by ITS1/ITS4 (where ITS stands for internal transcribed spacer) sequencing and the echinocandin target FKS1/FKS2 genes were sequenced. Susceptibility testing of caspofungin in the presence of fluphenazine was performed by a modified CLSI microbroth dilution method. The effect of the fluphenazine/caspofungin combination on heat stress (37°C or 40°C), oxidative stress (0.2 and 0.4 mM menadione) and biofilm formation (polyurethane catheter) was analysed. A Galleria mellonella model using blastospores (1 × 109 cfu/mL) was developed to evaluate the impact of this combination on larval survival. Results F659del was found in the FKS2 gene of both resistant strains. In these clinical isolates, fluphenazine increased susceptibility to caspofungin and reduced their thermotolerance. Furthermore, the fluphenazine/caspofungin combination significantly impaired biofilm formation in an in vitro polyurethane catheter model. All these features participated in the increasing survival of infected G. mellonella after combination treatment in comparison with caspofungin alone. Conclusions In a repurposing strategy, our findings confirm that calmodulin could provide a relevant target in life-threatening fungal infectious diseases.

In vitro and in vivo antifungal activities of ER-30346, a novel oral triazole with a broad antifungal spectrum.

1996 ◽  
Vol 40 (10) ◽  
pp. 2237-2242 ◽  
Author(s):  
K Hata ◽  
J Kimura ◽  
H Miki ◽  
T Toyosawa ◽  
T Nakamura ◽  
...  
Keyword(s):  
Amphotericin B ◽  
Candida Glabrata ◽  
Candida Parapsilosis ◽  
Good Activity ◽  
Time Curve ◽  
Concentration Time ◽  
Wide Range ◽  
Systemic Infections

ER-30346 is a novel oral triazole with a broad spectrum of potent activity against a wide range of fungi. ER-30346, with MICs at which 90% of the strains tested are inhibited (MIC90s) ranging from 0.025 to 0.78 microgram/ml, was 4 to 32 times more active than itraconazole, fluconazole, and amphotericin B against Candida albicans, Candida parapsilosis, and Candida glabrata. Against Candida tropicalis, ER-30346, with an MIC90 of 12.5 micrograms/ml, was 2 to > 8 times more active than itraconazole and fluconazole, but was 16 times less active than amphotericin B. ER-30346 (MIC90, 0.78 microgram/ml) was four to eight times more active than fluconazole and amphotericin B and had activity comparable to that of itraconazole against Trichosporon beigelli. The MIC90s of ER-30346 were 0.10 microgram/ml for Cryptococcus neoformans and 0.39 microgram/ml for Aspergillus fumigatus. ER-30346 was 2 to 8 times more active than itraconazole and amphotericin B and 32 to > 256 times more active than fluconazole. ER-30346 also showed good activity against dermatophytes, with MICs ranging from 0.05 to 0.39 microgram/ml, and its activity was comparable to or 2 to 16 times higher than those of itraconazole and amphotericin B and > 32 times higher than that of fluconazole. In vivo activity was evaluated with systemic infections in mice. Against systemic candidiasis and cryptococcosis, ER-30346 was comparable in efficacy to fluconazole and was more effective than itraconazole. Of the drugs tested, ER-30346 was the most effective drug against systemic aspergillosis. We studied the levels of ER-30346 in mouse plasma. The maximum concentration of drug in plasma and the area under the concentration-time curve for ER-30346 showed good linearity over a range of doses from 2 to 40 mg/kg of body weight.

scholarly journals The Burkholderia pseudomallei ΔasdMutant Exhibits Attenuated Intracellular Infectivity and Imparts Protection against Acute Inhalation Melioidosis in Mice

2011 ◽  
Vol 79 (10) ◽  
pp. 4010-4018 ◽  
Author(s):  
Michael H. Norris ◽  
Katie L. Propst ◽  
Yun Kang ◽  
Steven W. Dow ◽  
Herbert P. Schweizer ◽  
...  
Keyword(s):  
Burkholderia Pseudomallei ◽  
Cell Model ◽  
Single Copy ◽  
Wild Type ◽  
Live Attenuated Vaccine ◽  
Content Type ◽  
Life Threatening ◽  
A Cell ◽  
Bioterrorism Agent

ABSTRACTBurkholderia pseudomallei, the cause of serious and life-threatening diseases in humans, is of national biodefense concern because of its potential use as a bioterrorism agent. This microbe is listed as a select agent by the CDC; therefore, development of vaccines is of significant importance. Here, we further investigated the growth characteristics of a recently createdB. pseudomallei1026b Δasdmutantin vitro, in a cell model, and in an animal model of infection. The mutant was typified by an inability to grow in the absence of exogenous diaminopimelate (DAP); upon single-copy complementation with a wild-type copy of theasdgene, growth was restored to wild-type levels. Further characterization of theB. pseudomalleiΔasdmutant revealed a marked decrease in RAW264.7 murine macrophage cytotoxicity compared to the wild type and the complemented Δasdmutant. RAW264.7 cells infected by the Δasdmutant did not exhibit signs of cytopathology or multinucleated giant cell (MNGC) formation, which were observed in wild-typeB. pseudomalleicell infections. The Δasdmutant was found to be avirulent in BALB/c mice, and mice vaccinated with the mutant were protected against acute inhalation melioidosis. Thus, theB. pseudomalleiΔasdmutant may be a promising live attenuated vaccine strain and a biosafe strain for consideration of exclusion from the select agent list.

scholarly journals Gasdermin D restricts Burkholderia cenocepacia infection in vitro and in vivo

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shady Estfanous ◽  
Kathrin Krause ◽  
Midhun N. K. Anne ◽  
Mostafa Eltobgy ◽  
Kyle Caution ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Critical Role ◽  
In Vitro Study ◽  
Burkholderia Cenocepacia ◽  
Inflammasome Activation ◽  
Bacterial Survival ◽  
Life Threatening ◽  
Systemic Infections

AbstractBurkholderia cenocepacia (B. cenocepacia) is an opportunistic bacterium; causing severe life threatening systemic infections in immunocompromised individuals including cystic fibrosis patients. The lack of gasdermin D (GSDMD) protects mice against endotoxin lipopolysaccharide (LPS) shock. On the other hand, GSDMD promotes mice survival in response to certain bacterial infections. However, the role of GSDMD during B. cenocepacia infection is not yet determined. Our in vitro study shows that GSDMD restricts B. cenocepacia replication within macrophages independent of its role in cell death through promoting mitochondrial reactive oxygen species (mROS) production. mROS is known to stimulate autophagy, hence, the inhibition of mROS or the absence of GSDMD during B. cenocepacia infections reduces autophagy which plays a critical role in the restriction of the pathogen. GSDMD promotes inflammation in response to B. cenocepacia through mediating the release of inflammasome dependent cytokine (IL-1β) and an independent one (CXCL1) (KC). Additionally, different B. cenocepacia secretory systems (T3SS, T4SS, and T6SS) contribute to inflammasome activation together with bacterial survival within macrophages. In vivo study confirmed the in vitro findings and showed that GSDMD restricts B. cenocepacia infection and dissemination and stimulates autophagy in response to B. cenocepacia. Nevertheless, GSDMD promotes lung inflammation and necrosis in response to B. cenocepacia without altering mice survival. This study describes the double-edged functions of GSDMD in response to B. cenocepacia infection and shows the importance of GSDMD-mediated mROS in restriction of B. cenocepacia.

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