Daiane Flores Dalla Lana

Evaluation of 8-Hydroxyquinoline Derivatives as Hits for Antifungal Drug Design

Abstract Clioquinol is an 8‐hydroxyquinoline derivative that was widely used from the 1950s to 1970s as an oral antiparasitic agent. In 1970, the oral forms were withdrawn from the market due to reports of toxicity, but topical formulations for antifungal treatment remained available. Thus, the purpose of this study was to evaluate the toxicity, anti‐Candida and antidermatophyte activity and to determine pharmacodynamic characteristics of clioquinol and other 8‐hydroxyquinoline derivatives (8‐hydroxy‐5‐quinolinesulfonic acid and 8‐hydroxy‐7‐iodo‐5‐quinolinesulfonic acid). Antifungal activity was tested by broth microdilution and the fungicidal or fungistatic effect was checked by a time‐kill assay. Permeation and histopathological evaluation were performed in Franz diffusion cells with ear skin of pigs and examined under light microscopy. An HET‐CAM test was used to determine the potential irritancy. The three compounds were active against all isolates showing anti‐Candida and antidermatophyte activity, with MIC ranges of 0.031‐2 &mgr;g/ml, 1‐512 &mgr;g/ml, and 2‐1024 &mgr;g/ml for clioquinol, 8‐hydroxy‐5‐quinolinesulfonic acid, and 8‐hydroxy‐7‐iodo‐5‐quinolinesulfonic acid, respectively. All compounds showed fungistatic effect for Candida, 8‐hydroxy‐5‐quinolinesulfonic acid, and 8‐hydroxy‐7‐iodo‐5‐quinolinesulfonic acid showed a fungicidal effect for M. canis and T. mentagrophytes, and clioquinol showed a fungicidal effect only for T. mentagrophytes. Furthermore, they presented a fungicidal effect depending on the time and concentration. The absence of lesions was observed in histopathological evaluation and no compound was irritating. Moreover, clioquinol and 8‐hydroxy‐5‐quinolinesulfonic acid accumulated in the epithelial tissue, and 8‐hydroxy‐7‐iodo‐5‐quinolinesulfonic acid had a high degree of permeation. In conclusion, 8‐hydroxyquinoline derivatives showed antifungal activity and 8‐hydroxy‐5‐quinolinesulfonic acid demonstrated the potential for antifungal drug design.

Reversal of fluconazole resistance induced by a synergistic effect with Acca sellowiana in Candida glabrata strains

Abstract Context: The increased incidence of non-albicans Candida (NAC) resistant to fluconazole (FLZ) makes it necessary to use new therapeutic alternatives. Acca sellowiana (O.berg) Burret (Myrtaceae) is a guava with several proven biological activities. The interaction with fluconazole can be a feasible alternative to overcome this resistance. Objective: This study evaluates the in vitro antifungal activity of fractions obtained from the lyophilized aqueous extract of the leaves of A. sellowiana against resistant strains of NAC. Materials and methods: The antifungal activity of the fractions was evaluated at 500 μg/mL by microdilution method. Checkerboard assay was performed to determine the effect of the combination of the F2 fraction and antifungal at concentrations: MIC/4, MIC/2, MIC, MIC × 2 and MIC × 4. Results: Candida glabrata showed the lowest MIC values (500–3.90 μg/mL) and the F2 active fraction was the most effective. The association of F2 with FLZ showed a strong synergistic effect (FICI ≤ 0.5) against 100% of C. glabrata resistant isolates. Moreover, the F2 active fraction has demonstrated that probably acts in the cell wall of these yeasts. There was no observed acute dermal toxicity of lyophilized aqueous extract of leaves of A. sellowiana on pig ear skin cells. Discussion and conclusion: The interaction between substances present in the F2 active fraction is possibly responsible for the antifungal activity presented by this fraction. This study is unprecedented and suggests that the combination of F2 active fraction and FLZ might be used as an alternative treatment for mucocutaneus infections caused by C. glabrata resistant.

Novas tendências de combate ao biofilme de Candida em próteses dentárias

Apesar de a especie Candida albicans ser efetivamente o microrganismo mais frequentemente associado a estomatite protetica, as especies de Candida nao albicans ja foram isoladas nas superficies de dentaduras e da mucosa oral de individuos com essa lesao eritematosa. A virulencia das especies de Candida e a capacidade de adesao a polimeros acrilicos sao condicoes previas para a colonizacao e o desenvolvimento de biofilmes em superficies de dentaduras. Estudos recentes focam na tentativa de modificacao das resinas acrilicas para diminuir a adesao de cepas patogenicas e formadoras de biofilme do genero Candida spp. Dentro desse aspecto, esta revisao sistematiza o atual panorama epidemiologico da estomatite protetica associada ao uso de proteses dentarias, bem como as atuais e novas opcoes de combate ao biofilme fungico especializado na adesao desse tipo de biomaterial. Palavras-chave: Candida spp.; biofilme; estomatite protetica; resina acrilica; tratamento

Candida auris: emergence and epidemiology of a highly pathogenic yeast

Candida auris is a multidrug-resistant emerging yeast, which was responsible for healthcare-associated infection outbreaks, and was cataloged as a new species in 2009, after being isolated from a patient’s ear canal secretion in Japan. Since the notification of this first occurrence, numerous cases have been reported throughout the world, including Brazil. C. auris affects mainly inpatients, patients in intensive care units, exposed to broad-spectrum antifungal medications and who make use of vascular catheters. Currently, this yeast is one of the main responsible for invasive infections in hospitals and has been cause of concern by authorities and organs due to its rapid dissemination and difficult treatment caused by its low susceptibility to antifungal agents traditionally used in clinical practice. As a contributor to the severity of infections associated with C. auris , the transmission mechanism is still unknown, which implies in a lack of control of the microorganism and high mortality rates. Thus, this literature review presents relevant information in order to alert the importance of C. auris as an etiological agent of systemic infections, as well as its epidemiology and the real challenges of the treatment. Keywords : Candida auris ; candidiasis; candidemia; multidrug-resistance; biofilm; epidemiology; diagnosis

Dermatofitoses: agentes etiológicos, formas clínicas, terapêutica e novas perspectivas de tratamento

As dermatofitoses tem ocorrencia mundial, sendo mais prevalentes em paises de clima tropical e subtropical. Dados epidemiologicos indicam que essas micoses estao entre as infeccoes fungicas de maior ocorrencia. O quadro clinico mais comum de dermatofitose inclui despigmentacao, placas anulares, prurido e perda de cabelo, com lesoes tipicamente conhecidas como tineas , ocasionadas por fungos filamentosos dermatofiticos de tres generos anamorficos: Microsporum , Trichophyton e Epidermophyton . O tratamento das dermatofitoses, em geral, esta relacionado ao uso de antifungicos topicos e/ou sistemicos, apresentando como problematica o surgimento de especies multirresistentes. Esta revisao aborda as dermatofitoses e seus agentes etiologicos de forma aprofundada em aspectos epidemiologicos, apresentando a importância clinica do tema, com enfase na causa, prevencao, tratamento e prognostico dessa micose cutânea. Palavras-chave : Dermatofitoses; dermatofitos; epidemiologia; tratamento