A new acridone with antifungal properties against Candida spp. and dermatophytes, and antibiofilm activity against C. albicans.

AIM: The increase in the number of fungal infections worldwide, coupled with the limitations of current antifungal chemotherapy, demand the development of safe and effective new antifungals. Here, we presented the synthesis of a novel acridone (M14) and its antifungal properties against Candida and dermatophytes species. METHODS AND RESULTS: A series of 17 acridones was designed, synthesized and tested for its antifungal activity. The minimum inhibitory concentration (MIC) was determined by the broth microdilution method. Only the acridone M14 showed growth-inhibitory activity against reference strains and clinical isolates of Candida and dermatophytes, with MIC range of 7·81-31·25 µg ml-1 . Moreover, M14 exhibited fungicidal activity and prevented biofilm formation by C. albicans as well as reduced the viability of preformed biofilms, even at sub-MICs. The confocal laser scanning microscopy analysis revealed that C. albicans hyphal growth was completely inhibited in the presence of M14. Similarly, there was a severe inhibition on hyphal growth of Trichophyton rubrum. We also found that M14 has relatively low toxicity to human fibroblasts. CONCLUSIONS: The new acridone M14 has antifungal properties against Candida spp. and dermatophytes, and antibiofilm activity against C. albicans. In addition, M14 is relatively selective to fungal cells compared to human normal cells. SIGNIFICANCE AND IMPACT OF THE STUDY: Because of its in vitro antifungal activity, anti-Candida biofilm effect and moderate cytotoxicity towards normal human cell, M14 may serve as a valuable lead compound to develop a new antifungal agent.

Identification and antifungal susceptibility of fungi isolated from dermatomycoses.

BACKGROUND: Dermatomycoses are superficial fungal infections of the skin, hair and nails that affect more than 20-25% of the people worldwide. These infections can be caused by yeasts, dermatophytes and non-dermatophyte filamentous fungi (NDFF) and are considered a public health problem. Despite this, few studies have investigated the prevalence and antifungal susceptibility of causative agents of dermatomycoses in the developing world. OBJECTIVES: The aims of this study were to identify and determine the antifungal susceptibility profile of yeast and filamentous fungi isolated from dermatomycoses in Uberaba, Minas Gerais, Brazil. METHODS: Specimens were obtained from patients with clinically diagnosed and laboratory confirmed dermatomycosis between July 2009 and July 2011. Fungal identification was based on classical methods and antifungal susceptibility testing was performed by broth microdilution method. RESULTS: Of the 216 fungal isolates, 116 (53.8%) were yeasts, 70 (32.4%) dermatophytes and 30 (13.8%) NDFF. Onychomycosis was the most common clinical condition. Candida parapsilosis (24.1%) and Trichophyton rubrum (17.1%) were the fungi most frequently isolated. Voriconazole, ketoconazole and itraconazole were the most potent antifungal agents against yeast, whereas terbinafine, voriconazole and itraconazole had a high in vitro activity against dermatophytes. Overall, the antifungal agents had little or no activity against NDFF and the highest minimum inhibitory concentrations were those against Fusarium spp. CONCLUSION: Yeasts, particularly C. parapsilosis, play an important role as causative agents of dermatomycosis in our region. Our results suggest that the antifungal susceptibility testing coupled with proper identification of the fungi may be useful to assist clinicians in determining the appropriate therapy for dermatomycoses.

Structural analysis of two HLA-DR-presented autoantigenic epitopes: crucial role of peripheral but not central peptide residues for T-cell receptor recognition.

Specific and major histocompatibility complex (MHC)-restricted T-cell recognition of antigenic peptides is based on interactions of the T-cell receptor (TCR) with the MHC alpha helices and solvent exposed peptide residues termed TCR contacts. In the case of MHC class II-presented peptides, the latter are located in the positions p2/3, p5 and p7/8 between MHC anchor residues. For numerous epitopes, peptide substitution studies have identified the central residue p5 as primary TCR contact characterized by very low permissiveness for peptide substitution, while the more peripheral positions generally represent auxiliary TCR contacts. In structural studies of TCR/peptide/MHC complexes, this has been shown to be due to intimate contact between the TCR complementarity determining region (CDR) three loops and the central peptide residue. We asked whether this model also applied to two HLA-DR presented epitopes derived from an antigen targeted in type 1 diabetes. Large panels of epitope variants with mainly conservative single substitutions were tested for human leukocyte antigen (HLA) class II binding affinity and T cell stimulation. Both epitopes bind with high affinity to the presenting HLA-DR molecules. However, in striking contrast to the standard distribution of TCR contacts, recognition of the central p5 residue displayed high permissiveness even for non-conservative substitutions, while the more peripheral p2 and p8 TCR contacts showed very low permissiveness for substitution. This suggests that intimate TCR interaction with the central peptide residue is not always required for specific antigen recognition and can be compensated by interactions with positions normally acting as auxiliary contacts.