Nitric Oxide-Releasing Nanoparticles Are Similar to Efinaconazole in Their Capacity to Eradicate Trichophyton rubrum Biofilms

Abstract

Filamentous fungi such as Trichophyton rubrum and T. mentagrophytes, the main causative agents of onychomycosis, have been recognized as biofilm-forming microorganisms. Nitric oxide-releasing nanoparticles (NO-np) are currently in development for the management of superficial and deep bacterial and fungal infections, with documented activity against biofilms. In this context, this work aimed to evaluate, for the first time, the in vitro anti-T. rubrum biofilm potential of NO-np using standard ATCC MYA-4438 and clinical BR1A strains and compare it to commonly used antifungal drugs including fluconazole, terbinafine and efinaconazole. The biofilms formed by the standard strain produced more biomass than those from the clinical strain. NO-np, fluconazole, terbinafine, and efinaconazole inhibited the in vitro growth of planktonic T. rubrum cells. Similarly, NO-np reduced the metabolic activities of clinical strain BR1A preformed biofilms at the highest concentration tested (SMIC50 = 40 mg/mL). Scanning electron and confocal microscopy revealed that NO-np and efinaconazole severely damaged established biofilms for both strains, resulting in collapse of hyphal cell walls and reduced the density, extracellular matrix and thickness of the biofilms. These findings suggest that biofilms should be considered when developing and testing new drugs for the treatment of dermatophytosis. Development of a biofilm phenotype by these fungi may explain the resistance of dermatophytes to some antifungals and why prolonged treatment is usually required for onychomycosis.

Treatment of onychomycosis in an era of antifungal resistance: Role for antifungal stewardship and topical antifungal agents

“…Moreover, efinaconazole has demonstrated the ability to reduce the density and thickness of T . rubrum biofilms in vitro, 115 which may provide greater access to the site of infection in onychomycosis.…”

State-of-the-Art and Perspectives for Nanomaterials Combined with Nitric Oxide Donors: From Biomedical to Agricultural Applications

“…These RNS interact with microbe proteins through iron–sulfur clusters, heme moieties, amine, and thiols . As a small and lipophilic molecule, NO easily crosses physiological barriers, reaching target pathogen cells . Indeed, NO is synthesized by activated macrophages in the combat of invading microbes …”

“…87 As a small and lipophilic molecule, NO easily crosses physiological barriers, reaching target pathogen cells. 88 Indeed, NO is synthesized by activated macrophages in the combat of invading microbes. 89 The combination of NO donors with nanomaterials significantly enhances the antimicrobial activity of NO, allowing the design of viable approaches to deliver therapeutic amounts of NO directly to the infected site of application.…”

Updated Perspectives on the Diagnosis and Management of Onychomycosis

“…Topical medications for onychomycosis treatment are becoming increasingly popular because they may penetrate biofilms, have lower risks of drug–drug interactions given there is little to no systemic absorption of the medication, and do not require laboratory monitoring. 88 , 96 , 131 , 132 Topical therapies must penetrate the nail plate to reach the transungual space where the fungus resides and applied concentrations must therefore be adequate to retain the minimal inhibitory concentration. 1 , 93 There are barriers to penetration, including slow growth and thickness of the nail, a hard nail plate that functions as a concentrated hydrogel, an impermeable dense network of keratin fibers, and nails in diseased states (ie, thickened nail or nail plates that are detached from the nail bed).…”