Abstract
The growing number of oral infections caused by the Candida species are becoming harder to treat as the commonly used antibiotics become less effective. This drawback has led to the search for alternative strategies of treatment, which include the use of antifungal molecules derived from natural products. Herein, crotoxin (CTX), the main toxin of Crotalus durissus terrificus venom, was challenged against Candida tropicalis (CBS94) and Candida dubliniensis (CBS7987) strains by in vitro antimicrobial susceptibility tests. Minimum inhibitory concentration (MIC), minimum fungicidal concentration (MFC), and inhibition of biofilm formation were evaluated after CTX treatment. In addition, CTX-induced cytotoxicity in HaCaT cells was assessed by MTT (3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide) colorimetric assay. Native CTX showed a higher antimicrobial activity (MIC = 47 μg/mL) when compared to CTX-containing mouthwash (MIC = 750 μg/mL) and nystatin (MIC = 375 μg/mL). Candida spp biofilm formation was more sensitive to both CTX and CTX-containing mouthwash (IC100 = 12 μg/mL) when compared to nystatin (IC100 > 47 μg/mL). Moreover, significant membrane permeabilization at concentrations of 1.5 and 47 µg/mL was observed. Native CTX was less cytotoxic to HaCaT cells than CTX-containing mouthwash or nystatin between 24 and 48 h. These preliminary findings highlight the potential use of CTX in the treatment of oral candidiasis caused by resistant strains.
Highlights
Crotoxin (CTX) is a heterodimeric protein with 16 possible isoforms, consisting of a non-covalent association of a small acidic, non-enzymatic and non-toxic subunit (CA, named crotapotin) with a basic and weakly toxic phospholipase A2 subunit (CB, named PLA2 ) [1]
We found that the number of colony-forming units (CFU)/mL of both Candida strains was significantly reduced when 1.5 μg/mL of native CTX was tested, after 24 and 48 h of treatment
CTX was shown to modulate calcium signaling [2,34,35], which may account for the increase in HaCaT cell viability induced by low concentrations of CTX. The elucidation of such an effect would require more detailed studies concerned with the complex intracellular signaling pathways. This is a preliminary study for the assessment of the antimicrobial and antibiofilm activities of native
Summary
Crotoxin (CTX) is a heterodimeric protein with 16 possible isoforms, consisting of a non-covalent association of a small acidic, non-enzymatic and non-toxic subunit (CA, named crotapotin) with a basic and weakly toxic phospholipase A2 subunit (CB, named PLA2 ) [1]. Extensive research has been carried out on both CTX and its subunits to identify biomedical applications, such as immunomodulatory, antitumor, analgesic, and antimicrobial, the high systemic toxicity of this protein still represents a barrier to its clinical use [2,3]. Considering the therapeutic potential of CTX, the need to develop alternative forms of CTX clinical applications is of high-priority. Considered a broad-spectrum antimicrobial drug with low intestinal absorption, its systemic application is not feasible. It is widely used as a topical antiseptic for hand and wound disinfection, and is used in the composition of mouthwashes with a low incidence of toxicity or side effects [4,5]
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