| Congresso Brasileiro de Microbiologia 2023 | Resumo: 415-2 | ||||
Resumo:Onychomycosis (OM) is an extremely common and difficult-to-treat fungal nail infection that causes nail disfigurement, pain, associated infections, and psychosocial effects that negatively impact quality of life. The dermatophyte Trichophyton rubrum is the most common causative agent, but OM can also be caused by other dermatophytes, such as T. mentagrophytes, non-dermatophytes, such as Aspergillus flavus, or yeasts, such as Candida albicans. Conventional treatment of OM involves topical or systemic administration of antifungal drugs, but each approach has significant shortcomings with complete cure rates of less than 30% and 60%, respectively. Besides the issue of drug resistance and multiple pharmacological limitations of both systemic and topical conventional therapy, systemic antifungals are generally expensive and associated with severe adverse effects, while topic antifungals usually are limited by difficulties in delivering the drug through the nail plate, which is a highly keratinized, difficult-to-penetrate barrier. Taken together, these problems demonstrate the urgent need for alternative therapeutic options. Micro- and nano-drug delivery systems (DDS) are an interesting alternative mainly because they offer a chance to avoid conventional pharmacological limitations, functioning as a controlled and specific DDS as well as offer enhanced penetration due to the nature of the particles. In addition, novel DDS also provide the opportunity to deliver alternative molecules with antimicrobial effects, such as nitric oxide (NO). With this in mind, a silica microparticle DDS that stores and effectively slowly releases NO (zMP-NO) was developed by our group, with preliminary studies with a first-generation zMP-NO demonstrating efficacy against T. rubrum and C. albicans as well as diverse antibiotic-resistant bacterial species. In this study, our second-generation zMP-NO, which was improved for NO loading and manufacturability, was tested against a comprehensive library of clinical isolates of T. rubrum, T. mentagrophytes, A. flavus and C. albicans with the objective of determining minimum inhibitory and minimum fungicidal concentrations (MIC s and MFCs, respectively) according to CLSI protocols. Our results demonstrate activity ranging from 1 to 10 mg/ml in C. albicans, T. rubrum and T. mentagrophytes, while clinical and environmental isolates of A. flavus, which accounts for less than 1% of onychomycosis cases worldwide, seems to be resistant to zMP-NO therapy up to 20 mg/ml. Our preliminary data shows that NO concentrations of up to 1000 ug/ml can be achieved at the nail plate of cadaveric nails. Our preliminary cytotoxicity results using human dermal fibroblasts and keratinocytes have not shown toxicity to date. In summary, our preliminary results demonstrate zMP-NO efficacy in vitro, and this phase I study is resulting in a prototype formulation with defined concentrations for further formulation development and scale up. Palavras-chave: A. flavus, C. albicans, Microparticle, Nitric Oxide, Trichophyton sp | |||||