Improved Methods for Assessing Therapeutic Potential of Antifungal Agents against Dermatophytes and Their Application in the Development of NP213, a Novel Onychomycosis Therapy Candidate

• Published in: Antimicrobial agents and chemotherapy Vol. 63; no. 5
• Main Authors: Mercer, Derry K, Stewart, Colin S, Miller, Lorna, Robertson, Jennifer, Duncan, Vanessa M S, O'Neil, Deborah A
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01.05.2019
• Subjects: Antifungal Agents; Antifungal Agents - pharmacology; Antifungal Agents - therapeutic use; Arthrodermataceae - drug effects; Arthrodermataceae - pathogenicity; Experimental Therapeutics; Humans; Male; Microbial Sensitivity Tests; Microscopy, Electrochemical, Scanning; Nails - microbiology; Onychomycosis; Onychomycosis - drug therapy; Onychomycosis - microbiology; Tinea - drug therapy; Tinea - microbiology; tinea; onychomycosis; antifungal agents; antifungal susceptibility testing; dermatophytes; antimicrobial peptides
• ISSN: 0066-4804; 1098-6596
• DOI: 10.1128/AAC.02117-18

Onychomycosis is a common, difficult-to-treat nail infection that is mainly caused by dermatophytes. Current therapies are not wholly effective and are associated with manifold side effects. The development of treatments for onychomycosis is challenging because standard tests are not predictive of antifungal efficacy within the nail. We have developed a new antifungal agent, NP213, for the treatment of onychomycosis. NP213 is based on endogenous host defense peptides produced within the nail. We compared the activity of NP213 and existing antifungal agents using conventional antimicrobial susceptibility test (AST) systems and more physiologically relevant models based on the human nail. We observed that the standard AST methodologies failed to predict the efficacy of antifungal agents within the nail. To address that, we present a more physiologically relevant modified AST method. This method, alongside other standard assessments of activity (including mechanism-of-action and time-of-kill studies), better reflected the activity of NP213 and other antifungal agents within the nail than standard AST methods. NP213 is a rapidly acting, fungicidal peptide that is superior to existing antifungal agents It penetrated the nail more effectively than other antifungals, as confirmed by using an optimized nail infection model. The data presented here support the current clinical development status of NP213 as a novel agent for treating onychomycosis. We propose that the modified tests developed and applied for NP213 characterization are the most relevant to use for screening any potential therapeutic candidates for onychomycosis.