Membranolytic Activity Profile of Nonyl 3,4-Dihydroxybenzoate: A New Anti-Biofilm Compound for the Treatment of Dermatophytosis

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Costa-Orlandi, Caroline B. ; Bila, Niura M. ; Bonatti, Jean Lucas C. ; Vaso, Carolina O. ; Santos, Mariana B. ; Polaquini, Carlos R. ; Biasioli, Mariana M. Santoni M. ; Herculano, Rondinelli D. ; Regasini, Luis O. ; Fusco-Almeida, Ana Marisa ; Mendes-Giannini, Maria Jose S.

• Document type: Journal article
• Source: PHARMACEUTICS; v. 15, n. 5, p. 19-pg., 2023-05-04.

Abstract

The ability of dermatophytes to live in communities and resist antifungal drugs may explain treatment recurrence, especially in onychomycosis. Therefore, new molecules with reduced toxicity that target dermatophyte biofilms should be investigated. This study evaluated nonyl 3,4-dihydroxybenzoate (nonyl) susceptibility and mechanism of action on planktonic cells and biofilms of T. rubrum and T. mentagrophytes. Metabolic activities, ergosterol, and reactive oxygen species (ROS) were quantified, and the expression of genes encoding ergosterol was determined by real-time PCR. The effects on the biofilm structure were visualized using confocal electron microscopy, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). T. rubrum and T. mentagrophytes biofilms were susceptible to nonyl and resistant to fluconazole, griseofulvin (all strains), and terbinafine (two strains). The SEM results revealed that nonyl groups seriously damaged the biofilms, whereas synthetic drugs caused little or no damage and, in some cases, stimulated the development of resistance structures. Confocal microscopy showed a drastic reduction in biofilm thickness, and transmission electron microscopy results indicated that the compound promoted the derangement and formation of pores in the plasma membrane. Biochemical and molecular assays indicated that fungal membrane ergosterol is a nonyl target. These findings show that nonyl 3,4-dihydroxybenzoate is a promising antifungal compound. (AU)

• FAPESP's process: 17/18388-6 - Role of biofilm in the pathogenesis of dermatophytosis and development of combat strategies
• Grantee: Caroline Barcelos Costa Orlandi
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 19/22188-8 - Evaluation of the interaction of biofilms mono and dual-species of Candida spp and dermatophytes photodynamic therapy combined with 2-chalcone
• Grantee: Níura Madalena Bila
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)
• FAPESP's process: 18/02785-9 - Dermatophytes and Dermatophytosis: biofilm formation and development of control strategies.
• Grantee: Maria José Soares Mendes Giannini
• Support Opportunities: Regular Research Grants
• FAPESP's process: 20/15586-4 - Establishment of a three-dimensional model to determine the pharmacological efficacy and safety of nitrofuran and indoles derivatives and evaluation of Histoplasma capsulatum infection
• Grantee: Carolina Orlando Vaso
• Support Opportunities: Scholarships in Brazil - Doctorate (Direct)