Evaluation of Antifungal Efficacy in an Optimized Animal Model of<i>Trichophyton</i><i>mentagrophytes</i>-Dermatophytosis

Ghannoum, Mahmoud A.; Hossain, Mozammal; Long, Lisa; Mohamed, Sotohy; Reyes, Guadalupe; Mukherjee, Pranab K.

doi:10.1179/joc.2004.16.2.139

Cited by 49 publications

(53 citation statements)

References 12 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Lesions develop within 1 week and resolve after 3 to 4 weeks; chronic infections are rare. The lesions do respond to oral or topical antifungal treatments (17). There is obviously a need for alternate vertebrate and nonvertebrate models for dermatophyte pathogenesis.…”

Section: Tools For Hypothesis Testing In the Dermatophytesmentioning

confidence: 99%

“…Guinea pigs, mice, and rabbits are readily infected with zoophilic and geophilic dermatophytes, while anthropophilic species can occasionally induce a mild lesion. The most common model is the guinea pig (17,23,48). The basic procedure involves shaving the site of infection followed by heavily abrading or scarifying the area with a scalpel, razor blade, or sandpaper.…”

Section: Tools For Hypothesis Testing In the Dermatophytesmentioning

confidence: 99%

See 1 more Smart Citation

Generating and Testing Molecular Hypotheses in the Dermatophytes

et al. 2008

View full text Add to dashboard Cite

4Dermatophytes are the most common cause of fungal infections worldwide, impacting millions of individuals annually. In the United States alone, this translates into an economic impact on the health care system estimated to exceed $400 million a year for treatment alone (8,46). A recent survey conducted in 16 European countries has shown that more than one-third (35 to 40%) of the 90,000 participants were suffering with a fungal foot disease, mainly caused by dermatophytes (4). In a recent study, 22 to 50% of children in a U.S. day care center exhibited symptoms of dermatophytic scalp infections (2). Despite the prominence of dermatophyte infections and their resulting socioeconomic consequences, the research and medical communities lack a sophisticated understanding of these organisms' biology. Consequently, effective preventatives and therapeutics are lacking. These deficiencies are in large part due to the lack of genetic tools available for the study of these fungi and their host specificities. Several research efforts are now poised to produce genomic and molecular resources that will enable the molecular characterization of dermatophytes. These resources will soon be available for use by the larger research community to address many questions about the biology and pathogenesis of dermatophytes. This review will elaborate on the current status of these resources and their importance to the study of the dermatophytes. DERMATOPHYTE BIOLOGY AND DISEASEDisease. Tinea is a fungal infection of the skin, hair, or nails (reviewed in reference 34). The phrase is made specific by the addition of another term referring to a specific body location. Thus, the term "tinea pedis" refers to a fungal infection of the feet. Other tinea infections include tinea capitis (scalp or head), tinea corporis (body or trunk), and tinea unguium (nails, also known as onychomycosis). These terms do not indicate the infecting organism but the type of infection and the body location. Tinea infections are usually localized to the surface and are rarely systemic or disseminated.Fungal infections can be asymptomatic, they can be acute and severe, associated with inflammation, or they can be chronic (most common) (34). Tinea pedis usually occurs in the toe webs, with considerable scaling, fissuring, maceration, and erythema, accompanied by severe itching or burning. Tinea pedis can also localize to the sole of the foot, extending up the sides of the foot. The destruction of the skin barrier can result in bacterial superinfection. Nail infections are associated with thickening, discoloration, and pain. Scalp infections can cause irreversible hair loss.Organisms. All of the dermatophytes are ascomycetous molds, members of the class Euascomycetes that also includes Aspergillus species and the dimorphic fungi ( Fig. 1) (34). The dermatophytes are classified into three genera: Trichophyton, Microsporum, and Epidermophton. As can be seen in Fig. 2, the dermatophytes are a monophyletic clade, although the assigned genus designations within the clade ...

show abstract

Section: Tools For Hypothesis Testing In the Dermatophytesmentioning

confidence: 99%

Section: Tools For Hypothesis Testing In the Dermatophytesmentioning

confidence: 99%

Generating and Testing Molecular Hypotheses in the Dermatophytes

et al. 2008

View full text Add to dashboard Cite

show abstract

“…The dermatophytosis model was described previously (23). T. mentagrophytes ATCC 24953 isolates were subcultured on PDA plates and incubated at 30°C for 5 days.…”

mentioning

confidence: 99%

VT-1161 Dosed Once Daily or Once Weekly Exhibits Potent Efficacy in Treatment of Dermatophytosis in a Guinea Pig Model

Garvey

Hoekstra

Moore

et al. 2015

Antimicrob Agents Chemother

Self Cite

View full text Add to dashboard Cite

c Current therapies used to treat dermatophytoses such as onychomycosis are effective but display room for improvement in efficacy, safety, and convenience of dosing. We report here that the investigational agent VT-1161 displays potent in vitro antifungal activity against dermatophytes, with MIC values in the range of <0.016 to 0.5 g/ml. In pharmacokinetic studies supporting testing in a guinea pig model of dermatophytosis, VT-1161 plasma concentrations following single oral doses were dose proportional and persisted at or above the MIC values for at least 48 h, indicating potential in vivo efficacy with once-daily and possibly once-weekly dosing. Subsequently, in a guinea pig dermatophytosis model utilizing Trichophyton mentagrophytes and at oral doses of 5, 10, or 25 mg/kg of body weight once daily or 70 mg/kg once weekly, VT-1161 was statistically superior to untreated controls in fungal burden reduction (P < 0.001) and improvement in clinical scores (P < 0.001). The efficacy profile of VT-1161 was equivalent to those for doses and regimens of itraconazole and terbinafine except that VT-1161 was superior to itraconazole when each drug was dosed once weekly (P < 0.05). VT-1161 was distributed into skin and hair, with plasma and tissue concentrations in all treatment and regimen groups ranging from 0.8 to 40 g/ml (or g/g), at or above the MIC against the isolate used in the model (0.5 g/ml). These data strongly support the clinical development of VT-1161 for the oral treatment of onychomycosis using either once-daily or once-weekly dosing regimens. F ungal infections of the skin, nails, and hair by dermatophytes, yeasts, and nondermatophyte molds are a common occurrence (1-3), with an estimated worldwide prevalence of 20% to 25% (1). In a survey of ambulatory records in the United States, these infections necessitated an average of 4 million physician visits per year from 1995 to 2004 (4), and the majority of these infections were caused by dermatophytes. The worldwide distribution of causative fungi and types of infection are dependent on geography, environment, and cultural factors (1, 2). Consistent with most of Europe and the United States (1, 2), a recent retrospective study found that onychomycosis (also referred to as tinea unguium) was the most common dermatophyte infection and that the absolute number of onychomycosis cases increased 10-fold over a 40-year period (5). This increase can be partly explained by the increases of two at-risk populations, the elderly (6) and diabetics (7). The most common species causing onychomycosis in Europe and the United States are Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum (8).Current oral treatment options for superficial fungal infections include allylamines, such as terbinafine, and azole-based fungal sterol 14␣-demethylase (CYP51) inhibitors (8, 9). The azoles fall into two classes defined by the moiety that binds the heme iron within the active site of CYP51, the imidazoles (e.g., ketoconazole), which are rarely used orally due...

show abstract

“…The efficacy of EV-086 was determined in guinea pig model of Trichophyton menagrophytes skin dermatophytosis as previously described (27). Briefly, T. mentagrophytes ATCC 24953 was prepared as a suspension of 2 ϫ 10 8 conidia/ ml.…”

Section: S Cerevisiae Lipid Extraction and Analysismentioning

confidence: 99%

“…EV-086 has proven broad-spectrum and potent antifungal activity in vitro. In order to investigate its potential in vivo, EV-086 was tested in a guinea pig model of Trichophyton skin dermatophytosis as previously described (27).…”

Section: Table 2 Deleted Genes and Associated Biological Processes Ofmentioning

confidence: 99%

The Natural Diyne-Furan Fatty Acid EV-086 Is an Inhibitor of Fungal Delta-9 Fatty Acid Desaturation with Efficacy in a Model of Skin Dermatophytosis

Knechtle

Diefenbacher

Greve

et al. 2014

Antimicrob Agents Chemother

View full text Add to dashboard Cite

cHuman fungal infections represent a therapeutic challenge. Although effective strategies for treatment are available, resistance is spreading, and many therapies have unacceptable side effects. A clear need for novel antifungal targets and molecules is thus emerging. Here, we present the identification and characterization of the plant-derived diyne-furan fatty acid EV-086 as a novel antifungal compound. EV-086 has potent and broad-spectrum activity in vitro against Candida, Aspergillus, and Trichophyton spp., whereas activities against bacteria and human cell lines are very low. Chemical-genetic profiling of Saccharomyces cerevisiae deletion mutants identified lipid metabolic processes and organelle organization and biogenesis as targets of EV-086. Pathway modeling suggested that EV-086 inhibits delta-9 fatty acid desaturation, an essential process in S. cerevisiae, depending on the delta-9 fatty acid desaturase OLE1. Delta-9 unsaturated fatty acids-but not saturated fatty acids-antagonized the EV-086-mediated growth inhibition, and transcription of the OLE1 gene was strongly upregulated in the presence of EV-086. EV-086 increased the ratio of saturated to unsaturated free fatty acids and phosphatidylethanolamine fatty acyl chains, respectively. Furthermore, EV-086 was rapidly taken up into the lipid fraction of the cell and incorporated into phospholipids. Together, these findings demonstrate that EV-086 is an inhibitor of delta-9 fatty acid desaturation and that the mechanism of inhibition might involve an EV-086 -phospholipid. Finally, EV-086 showed efficacy in a guinea pig skin dermatophytosis model of topical Trichophyton infection, which demonstrates that delta-9 fatty acid desaturation is a valid antifungal target, at least for dermatophytoses. Healthy individuals are remarkably resistant to fungal infections. However, predisposing factors, such as age, immunosuppression, and underlying disease, weaken the immune system and render the host susceptible to fungal infections. Humid conditions and occlusive clothing further favor fungal growth on the skin. Fungal disease is therefore widespread and manifests in a spectrum from relatively mild dermatophytoses to serious systemic infections (1).Chemotherapy has proven to be a highly effective strategy for the treatment of fungal infections. The majority of agents applied for the treatment of dermatophytoses are from the allylamine and azole family. Triazoles, polyenes, and echinocandins are currently the main classes used to treat systemic fungal infections. Both the allylamines and the azoles inhibit the biosynthesis of ergosterol, an essential membrane component crucial for the physico-chemical properties of the membrane. Polyenes do not target the ergosterol biosynthetic pathway but directly bind to membrane sterols. The echinocandins target beta-glucan synthesis, which is essential for cell wall biosynthesis (2-4).Even though current chemotherapeutic strategies for the treatment of human fungal infections are effective, the widespread use of antifungal co...

show abstract

Evaluation of Antifungal Efficacy in an Optimized Animal Model ofTrichophytonmentagrophytes-Dermatophytosis

Cited by 49 publications

References 12 publications

Generating and Testing Molecular Hypotheses in the Dermatophytes

Generating and Testing Molecular Hypotheses in the Dermatophytes

VT-1161 Dosed Once Daily or Once Weekly Exhibits Potent Efficacy in Treatment of Dermatophytosis in a Guinea Pig Model

The Natural Diyne-Furan Fatty Acid EV-086 Is an Inhibitor of Fungal Delta-9 Fatty Acid Desaturation with Efficacy in a Model of Skin Dermatophytosis

Contact Info

Product

Resources

About