Characterization of Antifungal Activity and Nail Penetration of ME1111, a New Antifungal Agent for Topical Treatment of Onychomycosis

Tabata, Yuji; Takei-Masuda, Naomi; Kubota, Natsuki K.; Takahata, Sho; Ohyama, Makoto; Kaneda, Kaori; Iida, M.; Maebashi, Kazunori

doi:10.1128/aac.01739-15

Cited by 22 publications

(19 citation statements)

References 19 publications

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“…In fact, in vitro penetration studies conducted in Franz cell assays using human nail as well as a guinea pig model demonstrated that ME1111 concentrations in the nail following single and/or multiple applications were several orders of magnitude greater than the MFC 50 and MFC 90 determined in this study for three major dermatophytes species causing onychomycosis (25,26).…”

Section: Discussionmentioning

confidence: 99%

In Vitro Antifungal Activity of ME1111, a New Topical Agent for Onychomycosis, against Clinical Isolates of Dermatophytes

Ghannoum

Isham

Long

2015

Antimicrob Agents Chemother

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The treatment of onychomycosis has improved considerably over the past several decades following the introduction of the oral antifungals terbinafine and itraconazole. However, these oral agents suffer from certain disadvantages, including drug interactions and potential liver toxicity. Thus, there is a need for new topical agents that are effective against onychomycosis. ME1111 is a novel selective inhibitor of succinate dehydrogenase (complex II) of dermatophyte species, whose small molecular weight enhances its ability to penetrate the nail plate. In this study, we determined the antifungal activity of ME1111 against dermatophyte strains, most of which are known to cause nail infections, as measured by the MIC (n ‫؍‬ 400) and the minimum fungicidal concentration (MFC) (n ‫؍‬ 300). Additionally, we examined the potential for resistance development in dermatophytes (n ‫؍‬ 4) following repeated exposure to ME1111. Our data show that the MIC 90 of ME1111 against dermatophyte strains was 0.25 g/ml, which was equivalent to that of the comparators amorolfine and ciclopirox (0.25 and 0.5 g/ml, respectively). ME1111 was fungicidal at clinically achievable concentrations against dermatophytes, and its MFC 90 s against Trichophyton rubrum and Trichophyton mentagrophytes were 8 g/ml, comparable to those of ciclopirox. Furthermore, ME1111, as well as ciclopirox, did not induce resistance in 4 dermatophytes tested. Our studies show that ME1111 possesses potent antifungal activity and suggest that it has low potential for the development of resistance in dermatophytes.A mong superficial fungal infections, by far the most difficult to cure is toenail onychomycosis, which is responsible for 50% of all nail disease (1). Onychomycosis, a fungal nail infection affecting up to 13% of the general population (2-8) and 25% of the geriatric and diabetic population (7, 9, 10), is more than just a cosmetic problem. More importantly, onychomycosis has been reported to cause chronic pain associated with prolonged standing or walking and acute pain from footwear and cutting of the nails (11-13).The greatest predisposing risk factor for developing onychomycosis is advanced age, as the risk is reported to be 18.2% in patients 60 to 79 years of age compared to 0.7% in patients younger than 19 years of age. Further, men are up to 3 times more likely to have onychomycosis than women, though the reasons for this gender difference are not clear (5,14). Other risk factors include diabetes and conditions contributing to poor peripheral circulation (15). In fact, onychomycosis may represent an important predictor for the development of diabetic foot syndrome and foot ulcers (16). Patients who are immunosuppressed, such as those with HIV infection and those undergoing cancer therapy, are also predisposed to fungal nail infection (17).Several nonclinical risk factors also affect a person's chance of developing fungal nail infections. For example, toenail onychomycosis is not prevalent in tropical climates, presumably because people in those areas are...

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Section: Discussionmentioning

confidence: 99%

In Vitro Antifungal Activity of ME1111, a New Topical Agent for Onychomycosis, against Clinical Isolates of Dermatophytes

Ghannoum

Isham

Long

2015

Antimicrob Agents Chemother

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“…One case in point is the susceptibility testing of echinocandins against Aspergillus species. It was found that the minimum effective concentration, defined as the lowest concentration with visible morphological changes in growth patterns from filamentous to granular signifying abnormal hyphal growth, correlates better with clinical outcome than with the traditional MIC endpoint for echinocandins against Aspergillus strains (3,12,13).…”

Section: Discussionmentioning

confidence: 99%

“…ME1111 showed potent antifungal activity against Trichophyton rubrum and Trichophyton mentagrophytes (the major etiologic agents of onychomycosis) strains isolated in Japan and reference fungal strains with an MIC range of 0.12 to 0.5 mg/liter and with an MIC 50 and an MIC 90 of 0.5 mg/liter for both (3). ME1111 is a novel antifungal whose small molecular weight enhances its ability to penetrate the nail plate to reach the nail bed where the infection resides.…”

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confidence: 99%

Multilaboratory Evaluation of In Vitro Antifungal Susceptibility Testing of Dermatophytes for ME1111

et al. 2016

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h ME1111 is a novel small molecule antifungal agent under development for the topical treatment of onychomycosis. Standardization of the susceptibility testing method for this candidate antifungal is needed. Toward this end, 8 independent laboratories determined the interlaboratory reproducibility of ME1111 susceptibility testing. In addition, we subsequently identified 2 strains as quality control (QC) isolates for the method. In the reproducibility study, 5 blinded clinical strains each of Trichophyton rubrum, Trichophyton mentagrophytes, and Epidermophyton floccosum were tested, while the QC study tested 6 blinded T. rubrum or T. mentagrophytes ATCC strains. Testing was performed in frozen microtiter panels according to the Clinical and Laboratory Standards Institute (CLSI) M38-A2 methodology. In the reproducibility study, 9 of 15 clinical strains showed interlaboratory agreement of >90% at the 80% inhibition endpoint, with a range of agreement of 76.2% to 100%. In the QC study, 4 of the 6 ATCC strains showed interlaboratory agreement of >90%. ME1111 demonstrated excellent interlaboratory agreement when tested against dermatophytes. Based on this data, the CLSI Subcommittee on Antifungal Susceptibility Tests approved the susceptibility testing of ME1111 against dermatophytes according to M38-A2 methodology, which stipulates RPMI 1640 as the test medium, an inoculum size of 1 to 3 ؋ 10 3 CFU/ml, and an incubation time and temperature of 96 h at 35°C. The MIC endpoint should be 80% inhibition compared with the growth control. T. rubrum ATCC MYA-4438 and T. mentagrophytes ATCC 28185 were selected as QC isolates, with an acceptable range of 0.12 to 1 g/ml for the two strains. Currently available topical agents for the treatment of onychomycosis have low efficacy, and thus, there is a continued need for the development of new topical antifungals (1, 2). ME1111 showed potent antifungal activity against Trichophyton rubrum and Trichophyton mentagrophytes (the major etiologic agents of onychomycosis) strains isolated in Japan and reference fungal strains with an MIC range of 0.12 to 0.5 mg/liter and with an MIC 50 and an MIC 90 of 0.5 mg/liter for both (3). ME1111 is a novel antifungal whose small molecular weight enhances its ability to penetrate the nail plate to reach the nail bed where the infection resides. ME1111 inhibits succinate dehydrogenase (complex II) (4), and the fungicidal activity of ME1111 seems to be due to its inhibition of this enzyme, which leads to the blockade of ATP production.The standardized method for the susceptibility testing of dermatophytes was added to the Clinical and Laboratory Standards Institute (CLSI) approved standard M38-A2 following an interlaboratory study involving ciclopirox, fluconazole, griseofulvin, itraconazole, posaconazole, terbinafine, and voriconazole (5). However, this standard does not specifically reference ME1111.Therefore, in order for ME1111 to be included in this standard, an interlaboratory study was needed to evaluate the reproducibility of the MICs of ME111...

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“…It is highly active in vitro and in vivo against Trichophyton rubrum and Trichophyton mentagrophytes and shows excellent human nail permeability (1)(2)(3)(4). A previous study on its mechanism of action revealed that the molecular target of ME1111 was succinate dehydrogenase (complex II) in the mitochondrial electron transport system (5).…”

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Morphological Effect of the New Antifungal Agent ME1111 on Hyphal Growth of Trichophyton mentagrophytes, Determined by Scanning and Transmission Electron Microscopy

Nishiyama

Takahata

Abe

2017

Antimicrob Agents Chemother

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The effects of ME1111, a novel antifungal agent, on the hyphal morphology and ultrastructure of Trichophyton mentagrophytes were investigated by using scanning and transmission electron microscopy. Structural changes, such as pit formation and/or depression of the cell surface, and degeneration of intracellular organelles and plasmolysis were observed after treatment with ME1111. Our results suggest that the inhibition of energy production by ME1111 affects the integrity and function of cellular membranes, leading to fungal cell death. KEYWORDS antifungal agents, electron microscopy, mode of action, morphologyA new class of antifungal agent, ME1111 [2-(3, 5-dimethyl-1H-pyrazol-1-yl)-5-methylphenol] is being developed as a topical agent for onychomycosis. It is highly active in vitro and in vivo against Trichophyton rubrum and Trichophyton mentagrophytes and shows excellent human nail permeability (1-4). A previous study on its mechanism of action revealed that the molecular target of ME1111 was succinate dehydrogenase (complex II) in the mitochondrial electron transport system (5). However, its effects on the morphology and ultrastructure of hyphal cells are poorly understood. Electron microscopy appeared to be the most suitable approach for a better understanding of the essential events involved in the antidermatophytic action of ME1111. In this study, we investigated the effect of ME1111 on the ultrastructure of T. mentagrophytes grown in a liquid medium by scanning electron microscopy (SEM) and transmission electron microscopy (TEM).T. mentagrophytes TIMM 2789 was grown in RPMI 1640 medium and Sabouraud dextrose broth (SDB) for study with SEM and TEM, respectively. The MIC of ME1111 against this strain was 0.5 g/ml in RPMI 1640 medium and 0.25 g/ml in SDB, based on the broth microdilution method (CLSI document M38-A2) (6). Conidia of T. menta-

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Characterization of Antifungal Activity and Nail Penetration of ME1111, a New Antifungal Agent for Topical Treatment of Onychomycosis

Cited by 22 publications

References 19 publications

In Vitro Antifungal Activity of ME1111, a New Topical Agent for Onychomycosis, against Clinical Isolates of Dermatophytes

In Vitro Antifungal Activity of ME1111, a New Topical Agent for Onychomycosis, against Clinical Isolates of Dermatophytes

Multilaboratory Evaluation of In Vitro Antifungal Susceptibility Testing of Dermatophytes for ME1111

Morphological Effect of the New Antifungal Agent ME1111 on Hyphal Growth of Trichophyton mentagrophytes, Determined by Scanning and Transmission Electron Microscopy

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