Efficacy of TAK-457, a Novel Intravenous Triazole, against Invasive Pulmonary Aspergillosis in Neutropenic Mice

Hayashi, Rina; Kitamoto, Naomi; Iizawa, Yuji; Ichikawa, Takashi; Itoh, Katsumi; Kitazaki, Tomoyuki; Okonogi, Kenji

doi:10.1128/aac.46.2.283-287.2002

Cited by 10 publications

(6 citation statements)

References 32 publications

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“…[10] Besides the marketed drug of Cresemba, many 1,2,4-triazolium salts have been developed as prodrugs from triazole fungicides. [4,17,[22][23][24] These 1,2,4-triazolium salts have good water solubility and can be rapidly and safely converted into antifungal triazole drugs in living organisms. In 2001, Ichikawa [4] et al synthesized a new antifungal prodrug 1 (TAK-457) for injection with sufficient solubility (4-10 mg/mL in 5 % glucose), stability (1.8 % of TKA-456 after 1 d in 5 % glucose), and high in vivo inhibitory index against Candida albicans TA and Aspergillus fumigatus 437, with the ED 50 (the dose of the test compound which allows 50 % survival of the infected mice) values of 0.62 and 4.49 mg/kg (Figure 2).…”

Section: Antifungal Activities Of Mono-124-triazolium Saltsmentioning

confidence: 99%

Bioactivities of Triazolium‐Based N‐Heterocyclic Carbene Salts

Song

Zou

Jin

et al. 2023

Chemistry A European J

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1,2,4-Triazolium salts are precursors of N-heterocyclic carbenes (NHCs), which have been extensively used as effective catalysts and ligands for both asymmetric and nonenantioselective reactions. Nevertheless, they are also a kind of quaternary ammonium compounds (QACs) that possess amphipathic properties. The unique chemical and physical properties of 1,2,4-triazolium salts have received significant attention from scientists focusing on the development of novel bioactive molecules as pesticides and medicines. It is timely and meaningful to summarize the bioactivities of 1,2,4triazolium salt derivatives against various bacteria, fungi, cancer cells, and other pathogens in the past 30 years. Meanwhile, the structure-activity relationship (SAR) of 1,2,4triazolium salts was also summarized. Finally, our perspective on the future development and applications of triazolium salts as agrichemicals or human drugs is presented.

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Section: Antifungal Activities Of Mono-124-triazolium Saltsmentioning

confidence: 99%

Bioactivities of Triazolium‐Based N‐Heterocyclic Carbene Salts

Song

Zou

Jin

et al. 2023

Chemistry A European J

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“…Mice were immunosuppressed with a single dose of the glucocorticoid triamcinolone acetonide (40 mg/kg of body weight injected subcutaneously in the nape of the neck on day Ϫ1) (14, 59) and a single dose of cyclophosphamide (150 mg/kg injected intraperitoneally on day Ϫ3) (12,18,19,24,30,47). The mice were anesthetized with 3.5% isofluorane and inoculated intranasally with 10 5 conidia on day 0, and mortality was monitored for the next 14 days.…”

Section: Methodsmentioning

confidence: 99%

Disruption of theAspergillus fumigatusGene Encoding Nucleolar Protein CgrA Impairs Thermotolerant Growth and Reduces Virulence

et al. 2004

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Aspergillus fumigatusCgrA is the ortholog of a yeast nucleolar protein that functions in ribosome synthesis. To determine how CgrA contributes to the virulence of A. fumigatus, a ⌬cgrA mutant was constructed by targeted gene disruption, and the mutant was reconstituted to wild type by homologous introduction of a functional cgrA gene. The ⌬cgrA mutant had the same growth rate as the wild type at room temperature. However, when the cultures were incubated at 37°C, a condition that increased the growth rate of the wild-type and reconstituted strains approximately threefold, the ⌬cgrA mutant was unable to increase its growth rate. The absence of cgrA function caused a delay in both the onset and rate of germination at 37°C but had little effect on germination at room temperature. The ⌬cgrA mutant was significantly less virulent than the wild-type or reconstituted strain in immunosuppressed mice and was associated with smaller fungal colonies in lung tissue. However, this difference was less pronounced in a Drosophila infection model at 25°C, which correlated with the comparable growth rates of the two strains at this temperature. To determine the intracellular localization of CgrA, the protein was tagged at the C terminus with green fluorescent protein, and costaining with propidium iodide revealed a predominantly nucleolar localization of the fusion protein in living hyphae. Together, these findings establish the intracellular localization of CgrA in A. fumigatus and demonstrate that cgrA is required for thermotolerant growth and wild-type virulence of the organism.Aspergillus fumigatus is a saprophytic filamentous fungus that inhabits soil, water, and organic debris, where it has an essential role in the recycling of carbon and nitrogen (37). The organism propagates itself by the release into the air of high concentrations of asexual spores (conidia), which are unavoidably inhaled on a daily basis (26,46). Since the conidia are efficiently cleared by normal defenses, their inhalation is of minor consequence to healthy individuals. However, in the absence of adequate host immunity, the conidia germinate into highly invasive hyphae that cause severe lung damage and eventually disseminate to other organs. Patients with depressed immunity are at increased risk for infection with A. fumigatus, and the prognosis for invasive disease is very poor in these individuals (40). Of particular concern is the rising incidence of aspergillosis, a situation that has arisen as a consequence of aggressive cancer treatments and the widespread use of potent immunosuppressive regimens that support organ transplantation (33,44,54,58).Since A. fumigatus conidia are no more prevalent in the environment than the spores of some nonpathogenic molds (34), it is generally assumed that the organism has unique features that allow it to survive in humans, and thermotolerance has long been suspected to play a role (37). As a major component of the biomass in a self-heating compost pile, A. fumigatus has evolved mechanisms that allow it to grow we...

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“…The murine model described here is unique in that infection is initiated with a relatively small infectious inoculum, and consequently, the duration of infection is significantly longer than in models of IA which use a higher inoculum (10 4 to 10 9 depending on immunosuppressive regimen and strain of A. fumigatus) to initiate infection and result in a more precipitous course of disease (3,5,7). The initiation of infection with an inoculum that approximates that of human infection has important implications for the testing of novel therapeutics and diagnostic strategies.…”

Section: Efficacy Of Ambmentioning

confidence: 99%

Novel Inhalational Murine Model of Invasive Pulmonary Aspergillosis

Sheppard¹,

Rieg²,

Chiang³

et al. 2004

Antimicrob Agents Chemother

130

135

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We developed a novel model of invasive aspergillosis (IA) that recapitulates human disease. Mice were immunosuppressed with cyclophosphamide and cortisone acetate and then infected in an aerosol chamber. This procedure reproducibly delivered 1 ؋ 10 3 to 3 ؋ 10 3 conidia to the lungs. Lethal pulmonary IA developed over 2 weeks and was prevented by amphotericin B.The last 2 decades have seen a rise in the incidence of invasive infections due to Aspergillus species, particularly A. fumigatus (4,8). Despite the development of new antifungal agents, mortality from invasive aspergillosis (IA) remains at least 50% (1, 2, 6). As a result, there is an urgent need for further study of this disease and the development of new clinical strategies to reduce mortality associated with IA. A simple, reproducible animal model that recapitulates the pathogenesis of human IA is a critical tool for developing new methods to prevent, diagnose, and treat this disease (7).IA is initiated by the inhalation of small numbers of A. fumigatus conidia which, by virtue of their small size, evade the mucociliary barrier of the bronchial airways and are deposited in the pulmonary alveoli (7). In the immunosuppressed host, conidia germinate to produce invasive hyphal forms, which propagate by extension and invade local pulmonary tissues. Angioinvasion is a prominent histopathological and clinical feature of IA and is likely the mechanism for dissemination of hyphal fragments to other organs in a subset of patients.We have developed a murine model of invasive pulmonary aspergillosis that recapitulates many of the key factors of human IA. By using an inhalation chamber, a relatively small number of conidia are delivered by small-particle aerosol to immunocompromised mice. This delivery system is reproducible both among mice within an experiment and between experiments. This route of inoculation results in a lethal infection in 60 to 75% of animals within 16 days. Additionally, we show that amphotericin B (AMB) is protective in this model.Strains and media. A. fumigatus strain AF293 (a generous gift from P. Magee) was used for all experiments in this study. To prepare the inoculum, A. fumigatus was grown on Sabouraud dextrose agar plates for 2 weeks at 37°C. Conidia were collected by flooding the plates with sterile phosphate-buffered saline containing 0.2% (vol/vol) Tween 80. The conidia were concentrated by centrifugation and counted using a hemacytometer.Inhalation apparatus. To infect animals via inhalation, we adapted the aerosol chamber described by Pal and Horwitz (10) for use with A. fumigatus conidia (Fig. 1). Mice were introduced via a hinged doorway to a Plexiglas exposure chamber (South Bay Plastics, Torrance, Calif.). The inoculum was introduced by aerosolizing a conidial suspension with a smallparticle nebulizer (Hudson Micro Mist; Hudson RCI, Temecula, Calif.) driven by compressed air at 100 lb/in 2 . The nebulizer was connected to a channel that ran along the top of the chamber and vented the aerosol from the middle of the chamber c...

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Efficacy of TAK-457, a Novel Intravenous Triazole, against Invasive Pulmonary Aspergillosis in Neutropenic Mice

Cited by 10 publications

References 32 publications

Bioactivities of Triazolium‐Based N‐Heterocyclic Carbene Salts

Bioactivities of Triazolium‐Based N‐Heterocyclic Carbene Salts

Disruption of theAspergillus fumigatusGene Encoding Nucleolar Protein CgrA Impairs Thermotolerant Growth and Reduces Virulence

Novel Inhalational Murine Model of Invasive Pulmonary Aspergillosis

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