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

Abstract

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...

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

“…ME1111 demonstrated antifungal activity as potent as that of ciclopirox against clinical dermatophyte strains isolated from Japanese patients, including T. rubrum and T. mentagrophytes, which are common etiologic agents of onychomycosis (Table 1). These results are in line with the activity of ME1111 against clinical dermatophyte isolates obtained from patients in the United States (18), where the MIC 90 against the U.S. isolates was 0.25 mg/liter. The finding that the susceptibility of dermatophyte isolates obtained from the U.S. sites to ME1111 was similar to that of isolates from non-U.S. sites indicates that there is no difference 8% ciclopirox lacquer (Penlac) 6 0.00 Ϯ 0.00 5% amorolfine lacquer (Loceryl) 6 0.00 Ϯ 0.00 in ME1111 susceptibility among the dermatophyte species obtained worldwide.…”

“…Moreover, it was reported that the MICs of ME1111 against 7 strains of terbinafine-resistant T. rubrum were not elevated (18). Our study also demonstrated the potent activity of ME1111 against a terbinafine-resistant T. mentagrophytes strain.…”

“…To date, susceptibility to ME1111 has been measured against more than 500 strains of dermatophytes (400 strains were tested previously [18], and 109 strains were tested in this study), and the results show that none of the tested isolates have elevated ME1111 MICs. Moreover, it was reported that the MICs of ME1111 against 7 strains of terbinafine-resistant T. rubrum were not elevated (18).…”

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

“…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).…”

Mechanism of Action of ME1111, a Novel Antifungal Agent for Topical Treatment of Onychomycosis

“…Fig. 1) is a new agent discovered by Meiji Seika Pharma Co., Ltd. (Tokyo, Japan), that possesses potent in vitro antifungal activity against dermatophytes, such as Trichophyton rubrum and Trichophyton mentagrophytes, which are common causative organisms of onychomycosis (14,15). A small molecular weight is reported to be one of the important factors of a compound for nail penetration ability (16).…”