1346. The Tetrazole VT-1598 Is Efficacious in a Murine Model of Invasive Aspergillosis with a PK/PD Expected of a Mold-Active CYP51 Inhibitor

Abstract Background VT-1598 is a novel fungal CYP51 inhibitor with potent in vitro activity against yeast, mold, and endemic pathogenic fungi (Wiederhold, JAC, 2017). Its tetrazole-based rational drug design imparts much greater selectivity vs. human CYPs (Yates, BMCL, 2017), which could reduce human CYP-related side effects and DDIs. We report here VT-1598’s in vivo activity in an invasive aspergillosis (IA) model. Methods MIC was determined as outlined in CLSI M38-A2. Plasma PK was measured after 4 days of oral doses in neutropenic ICR mice without fungal inoculation. In vivo antifungal activity was determined in a tail-vein IA model in neutropenic mice inoculated with A. fumigatus (AF) ATCC 204305 (N = 10 per dose). Two separate studies were conducted, with oral VT-1598 treatment starting either 48 hours prior (prophylaxis) or 5 hours postinoculation (delayed), with 4 days of postinoculation dosing, and kidney fungal burden measured 1 day post last dose by both CFU and qPCR. Drug control was 10 mg/kg AmBisome i.v. Results The MIC for VT-1598 against AF 204305 was 0.25 μg/mL. The plasma PK of VT-1598 was linearly proportional between the 5 and 40 mg/kg once-daily doses, with AUCs of 155 and 1,033 μg h/mL for the two doses, respectively. VT-1598 was similarly effective in reducing fungal burden when given in delayed treatment compared with prophylaxis, and both studies demonstrated a full dose–response (i.e., no to full reduction of fungal burden). When comparing fungal burdens of each dose group to the fungal burden at the start of treatment, the dose of VT-1598 to achieve fungal stasis ranged from 20.5 to 25.9 mg/kg and to achieve a 1-log10 fungal kill ranged from 30.9 to 50.5 mg/kg. Using the previously measured mouse plasma binding (>99.9%), the free AUC /MIC values for stasis and 1-log10 kill ranged from 2.1–2.7 and 3.2–5.2, respectively. These values are within the range of 1–11 that have been reported for posaconazole and isavuconazole (Lepak, AAC, 2013). Conclusion VT-1598 had potent antifungal activity in a murine model of IA. The PK/PD relationship was the same as clinically used mold-active CYP51 agents, suggesting that it could have similar clinical efficacy. If correct, the tetrazole-based greater selectivity may significantly differentiate VT-1598 from current IA therapies. Disclosures E. P. Garvey, Viamet Pharmaceuticals, Inc.: Employee, Salary. A. Sharp, Evotec (UK) Ltd.: Employee, Salary. P. Warn, Evotec (UK) Ltd.: Employee, Salary. C. M. Yates, Viamet Pharmaceuticals, Inc.: Employee, Salary. R. J. Schotzinger, Viamet Pharmaceuticals, Inc.: Board Member and Employee, Salary.

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Efficacy of Voriconazole, Isavuconazole, Fluconazole, and Anidulafungin in the treatment of emerging Candida auris using an immunocompromised murine model of disseminated candidiasis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00549-21 ◽

2021 ◽

Author(s):

Ahmed Gamal ◽

Lisa Long ◽

Janet Herrada ◽

Jalal Aram ◽

Thomas S. McCormick ◽

...

Keyword(s):

Antifungal Activity ◽

Amphotericin B ◽

Murine Model ◽

Kidney Tissue ◽

Comparable Efficacy ◽

P Value ◽

Candida Auris ◽

Fungal Burden

Antifungal activity of anidulafungin, voriconazole, isavuconazole, and fluconazole in the treatment of Candida auris was determined in vitro and in vivo . Minimum inhibitory concentrations (MICs) for Anidulafungin, voriconazole, isavuconazole, fluconazole, and amphotericin B were 0.5, 1, >64, 0.25, and 4 μg/mL, respectively. Significant in vivo efficacy was observed in anidulafungin- and voriconazole-treated groups in survival and reduction in kidney tissue fungal burden compared to the untreated group ( P-value of < 0.001 and 0.044, respectively). Our data showed that anidulafungin and voriconazole had comparable efficacy against C. auris , whereas isavuconazole did not show significant in vivo activity.

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In Vitro and In Vivo Antifungal Activity of AmBisome Compared to Conventional Amphotericin B and Fluconazole against Candida auris

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.00306-21 ◽

2021 ◽

Author(s):

Janet Herrada ◽

Ahmed Gamal ◽

Lisa Long ◽

Sonia P. Sanchez ◽

Thomas S. McCormick ◽

...

Keyword(s):

Antifungal Activity ◽

Amphotericin B ◽

Kidney Tissue ◽

Treated Group ◽

Untreated Group ◽

Candida Auris ◽

Fungal Burden ◽

In Vivo Antifungal Activity

Antifungal activity of AmBisome against Candida auris was determined in vitro and in vivo. AmBisome showed MIC50 and MIC90 values of 1 and 2 μg/mL, respectively. Unlike conventional amphotericin B, significant in vivo efficacy was observed in the AmBisome 7.5 mg/kg -treated group in survival and reduction of kidney tissue fungal burden compared to the untreated group. Our data shows that AmBisome shows significant antifungal activity against C. auris in vitro as well as in vivo.

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New Triazole NT-a9 Has Potent Antifungal Efficacy against Cryptococcus neoformans In Vitro and In Vivo

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01628-19 ◽

2019 ◽

Vol 64 (2) ◽

Cited By ~ 1

Author(s):

Ren-Yi Lu ◽

Ting-Jun-Hong Ni ◽

Jing Wu ◽

Lan Yan ◽

Quan-Zhen Lv ◽

...

Keyword(s):

Cryptococcus Neoformans ◽

Amphotericin B ◽

Pathogenic Fungi ◽

Control Group ◽

Survival Times ◽

Content Type ◽

Fungal Burden ◽

Wide Range

ABSTRACT In the past decades, the incidence of cryptococcosis has increased dramatically, which poses a new threat to human health. However, only a few drugs are available for the treatment of cryptococcosis. Here, we described a leading compound, NT-a9, an analogue of isavuconazole, that showed strong antifungal activities in vitro and in vivo. NT-a9 showed a wide range of activities against several pathogenic fungi in vitro, including Cryptococcus neoformans, Cryptococcus gattii, Candida albicans, Candida krusei, Candida tropicalis, Candida glabrata, and Candida parapsilosis, with MICs ranging from 0.002 to 1 μg/ml. In particular, NT-a9 exhibited excellent efficacy against C. neoformans, with a MIC as low as 0.002 μg/ml. NT-a9 treatment resulted in changes in the sterol contents in C. neoformans, similarly to fluconazole. In addition, NT-a9 possessed relatively low cytotoxicity and a high selectivity index. The in vivo efficacy of NT-a9 was assessed using a murine disseminated-cryptococcosis model. Mice were infected intravenously with 1.8 × 106 CFU of C. neoformans strain H99. In the survival study, NT-a9 significantly prolonged the survival times of mice compared with the survival times of the control group or the isavuconazole-, fluconazole-, or amphotericin B-treated groups. Of note, 4 and 8 mg/kg of body weight of NT-a9 rescued all the mice, with a survival rate of 100%. In the fungal-burden study, NT-a9 also significantly reduced the fungal burdens in brains and lungs, while fluconazole and amphotericin B only reduced the fungal burden in lungs. Taken together, these data suggested that NT-a9 is a promising antifungal candidate for the treatment of cryptococcosis infection.

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Efficacies of Fluconazole, Caspofungin, and Amphotericin B in Candida glabrata-Infected p47phox−/− Knockout Mice

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.46.5.1240-1245.2002 ◽

2002 ◽

Vol 46 (5) ◽

pp. 1240-1245 ◽

Cited By ~ 39

Author(s):

Justina Y. Ju ◽

Cynthia Polhamus ◽

Kieren A. Marr ◽

Steven M. Holland ◽

John E. Bennett

Keyword(s):

Candida Albicans ◽

Amphotericin B ◽

Murine Model ◽

Knockout Mice ◽

Candida Glabrata ◽

Drug Efficacy ◽

Fungal Burden ◽

Lethal Infection

ABSTRACT Candida glabrata is the second leading cause of adult candidemia, resulting in high mortality. Amphotericin B is considered the treatment of choice, while the efficacy of fluconazole is controversial and caspofungin efficacy is unknown. To ascertain drug efficacy in vivo, the utility of a murine model of C. glabrata infection was investigated. C. glabrata was found to cause progressive, lethal infection when injected intravenously into C57BL/6 mice with reduced oxidative microbicidal capacity due to knockout of the p47phox gene. Spleen and kidney organ CFU counts were determined in groups of mice 2 days after the mice completed 6 days of daily intraperitoneal drug treatment, which began on the day of infection. Daily injections of fluconazole at 80 mg/kg did not reduce spleen or kidney CFU counts after infection with C. glabrata strains having in vitro fluconazole MICs of 2, 32, or 256 μg/ml compared to saline-treated controls. However, this fluconazole regimen reduced spleen CFU counts in mice infected with Candida albicans, an infection that is known to be responsive to fluconazole. Caspofungin at 5 mg/kg and amphotericin B at 5 mg/kg were both effective in reducing fungal burden in spleens and kidneys of C. glabrata-infected mice. Ten mice treated for 6 days with caspofungin at 1 mg/kg survived for 15 days, though all 10 saline-injected mice died or were so ill that they had to be sacrificed by 96 h postinfection. This murine model provided evidence of the efficacy of amphotericin B and caspofungin but not of fluconazole against C. glabrata infection.

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Enzyme regulation by biological disulfides

Bioscience Reports ◽

10.1007/bf01119803 ◽

1989 ◽

Vol 9 (5) ◽

pp. 593-604 ◽

Cited By ~ 17

Author(s):

Raul N. Ondarza

Keyword(s):

Drug Design ◽

Small Molecule ◽

Regulatory Mechanism ◽

Enzyme Regulation ◽

Rational Drug Design ◽

Host Cells ◽

Disulfide Exchange ◽

Rational Drug

More than a dozen enzymes have been found to be activated or inhibited in vitro by disulfide-exchange between the protein and small-molecule disulfides. Accordingly, thiol/disulfide ratio changes in vivo may be of great importance in the regulation of cellular metabolism. An awareness of this regulatory mechanism in both host cells and parasites, coupled with information on the presence or absence of key enzymes, may lead to rational drug design against certain diseases involving thiol intermediates, including trypanosomiasis.

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TINOSPORA CORDIFOLIA AQUEOUS EXTRACT AMELIORATES THE SYSTEMIC INFECTION OF ASPERGILLUS FUMIGATUS IN BALB/C MICE

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2019.v12i3.30984 ◽

2019 ◽

pp. 525-528 ◽

Cited By ~ 1

Author(s):

MASOOD A KHAN

Keyword(s):

Survival Rate ◽

Antifungal Activity ◽

Aspergillus Fumigatus ◽

Aqueous Extract ◽

Survival Data ◽

Systemic Infection ◽

Tinospora Cordifolia ◽

Fungal Burden

Objective: The present study was aimed to assess the antifungal activity of Tinospora cordifolia aqueous extract (TCAE) against Aspergillus fumigatus infection. Methods: TCAE was tested for in vitro antifungal activity against the isolates of A. fumigatus, Aspergillus flavus, and Aspergillus niger. To evaluate in vivo activity, various doses (10, 25, and 50 mg/kg) of TCAE were orally administered in A. fumigatus-infected mice for 7 days. The combination of prophylactic and therapeutic effect of TCAE was assessed by pre-treating the mice with 10 mg/kg of TCAE for 3 consecutive days before exposing them to A. fumigatus. Mice were treated with 10, 25, and 50 mg/kg doses of TCAE for 7 consecutive days’ post-A. fumigatus infection. The effectiveness of TCAE was evaluated by monitoring the survival rate and assessing the fungal burden in the kidney of the treated mice. Results: A. fumigatus-infected mice treated with TCAE at the doses of 25 and 50 mg/kg exhibited 50% and 20% survival rate, respectively, observed on day 40 post-treatment. Like to the survival data, the fungal burden was also found to be the lowest in the kidney of mice treated with TCAE at a dose of 50 mg/kg. The results showed that pre-treatment with TCAE (10 mg/kg) followed by post-infection treatment with 10, 25, and 50 mg/kg of TCAE for 7 days resulted in 40%, 50%, and 70% survival rate, respectively. Conclusions: These results suggest that TCAE may potentially be considered for its possible use in the treatment of the systemic infection of A. fumigatus.

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Efficacy of Delayed Therapy with Fosmanogepix (APX001) in a Murine Model of Candida auris Invasive Candidiasis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01120-19 ◽

2019 ◽

Vol 63 (11) ◽

Cited By ~ 13

Author(s):

Nathan P. Wiederhold ◽

Laura K. Najvar ◽

Karen J. Shaw ◽

Rosie Jaramillo ◽

Hoja Patterson ◽

...

Keyword(s):

Murine Model ◽

Invasive Candidiasis ◽

Pathogenic Fungi ◽

Candida Auris ◽

Pathogenic Yeast ◽

Once Daily ◽

Content Type ◽

Fungal Burden ◽

Fluconazole Resistant

ABSTRACT The emerging pathogenic yeast Candida auris is associated with antifungal resistance and high mortality. The novel antifungal agent manogepix (APX001A) inhibits glycosylphosphatidylinositol-anchored protein maturation and has demonstrated activity against numerous pathogenic fungi, including C. auris. Our objective was to evaluate the in vivo efficacy of fosmanogepix, the N-phosphonooxymethyl prodrug (APX001), following delayed initiation of therapy in a murine model of C. auris invasive candidiasis. Neutropenic mice were intravenously infected with a fluconazole-resistant clinical isolate of C. auris. Twenty-four hours postinoculation, treatment began with vehicle control, fosmanogepix (104 and 130 mg/kg of body weight by intraperitoneal injection three times daily, or intraperitoneal 260 mg/kg twice daily), fluconazole (20 mg/kg by oral gavage once daily), or caspofungin (intraperitoneal 10 mg/kg once daily) and continued for 7 days. Fungal burden was assessed via colony count in the kidneys and brains on day 8 in the fungal burden arm and on day 21 as the mice became moribund in the survival arm. Significant improvements in survival were observed in each group administered fosmanogepix and caspofungin. Similarly, reductions in fungal burden were also observed in both the kidneys and brains of mice treated with the highest dose of fosmanogepix in the fungal burden arm and in each fosmanogepix group and with caspofungin in the survival arm. In contrast, no improvements in survival or reductions in fungal burden were observed in mice treated with fluconazole. These results demonstrate that fosmanogepix is effective in vivo against fluconazole-resistant C. auris even when therapy is delayed.

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The celecoxib derivative AR-12 has broad spectrum antifungal activity in vitro and improves the activity of fluconazole in a murine model of cryptococcosis

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01061-16 ◽

2016 ◽

pp. AAC.01061-16 ◽

Cited By ~ 13

Author(s):

Kristy Koselny ◽

Julianne Green ◽

Louis DiDone ◽

Justin P. Halterman ◽

Annette W. Fothergill ◽

...

Keyword(s):

Antifungal Activity ◽

Small Molecules ◽

Broad Spectrum ◽

Murine Model ◽

Antifungal Drugs ◽

Dimorphic Fungi ◽

New Class ◽

Cancer Agent

Only one new class of antifungal drugs has been introduced into clinical practice in the last thirty years and, thus, the identification of small molecules with novel mechanisms of action is an important goal of current anti-infective research. Here, we describe the characterization of the spectrum of in vitro activity and in vivo activity of AR-12, a celecoxib-derivative which has been tested in a Phase I clinical trial as an anti-cancer agent. AR-12 inhibits fungal acetyl CoA synthetase in vitro and is fungicidal at concentrations similar to those achieved in human plasma. AR-12 has a broad spectrum of activity including active against yeasts (e.g.,C. albicans, non-albicansCandidaspp.,C. neoformans); molds (e.g.,Fusarium,Mucor), and dimorphic fungi (Blastomyces,Histoplasma, andCoccidioides) with minimum inhibitory concentrations of 2-4 μg/mL. AR-12 is also active against azole- and echinocandin-resistantCandidaisolates and sub-inhibitory AR-12 concentrations increase susceptibility of fluconazole- and echinocandin-resistantCandidaisolates. Finally, AR-12 also increases the activity of fluconazole in a murine model of cryptococcosis. Taken together, these data indicate that AR-12 represents a promising class of small molecules with broad spectrum antifungal activity.

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