A self-assembling peptide inhibits the growth and function of fungi via a wrapping strategy.

Fungal infections contribute substantially to human morbidity and mortality. A particular concern is the high rate of mortality associated with invasive fungal infections, which often exceeds 50.0% despite the availability of several antifungal drugs. Herein, we show a self-assembling antifungal peptide (AFP), which is able to bind to chitin on the fungal cell wall and in situ form AFP nanofibers, wrapping fungi. As a result, AFP limits the proliferation of fungi, slows down the morphological transformation of biphasic fungi, and inhibits the adhesion of fungi to host cells and the formation of biofilms. Compared to the broad-spectrum antifungal fluconazole, AFP achieved a comparable inhibitory effect (MIC50 = 3.5 µM) on fungal proliferation. In addition, AFP significantly inhibited the formation of fungal biofilms with the inhibition rate of 69.6% at 1 µM, better than fluconazole (17.2% at 1 µM). In a skin infection model of mice, it was demonstrated that AFP showed significantly superior efficacy to fluconazole. In the systemic candidiasis mouse model, AFP showed similar efficacy to first-line antifungal amphotericin B (AmpB) and anidulafungin (AFG). This study provides a promising wrapping strategy for anti-fungal infection.

Genome-wide profiling of piggyBac transposon insertion mutants reveals loss of the F1F0 ATPase complex causes fluconazole resistance in Candida glabrata.

Invasive candidiasis caused by non-albicans species has been on the rise, with Candida glabrata emerging as the second most common etiological agent. Candida glabrata possesses an intrinsically lower susceptibility to azoles and an alarming propensity to rapidly develop high-level azole resistance during treatment. In this study, we have developed an efficient piggyBac (PB) transposon-mediated mutagenesis system in C. glabrata to conduct genome-wide genetic screens and applied it to profile genes that contribute to azole resistance. When challenged with the antifungal drug fluconazole, PB insertion into 270 genes led to significant resistance. A large subset of these genes has a role in the mitochondria, including almost all genes encoding the subunits of the F1F0 ATPase complex. We show that deleting ATP3 or ATP22 results in increased azole resistance but does not affect susceptibility to polyenes and echinocandins. The increased azole resistance is due to increased expression of PDR1 that encodes a transcription factor known to promote drug efflux pump expression. Deleting PDR1 in the atp3Δ or atp22Δ mutant resulted in hypersensitivity to fluconazole. Our results shed light on the mechanisms contributing to azole resistance in C. glabrata. This PB transposon-mediated mutagenesis system can significantly facilitate future genome-wide genetic screens.

Assessment of the quality of compounded fluconazole capsules marketed in the region of Araraquara (SP, Brazil) / Avaliação da qualidade de cápsulas de fluconazol manipuladas comercializadas na região de Araraquara (SP, Brasil)

O controle de qualidade de fármacos desempenha um papel importante na saúde pública ao garantir segurança e eficácia de medicamentos. No sistema de saúde pública,as farmácias magistrais também são importantes. Elas fornecem medicamentos personalizados como produtos dermatológicos e doses específicas para crianças.Infelizmente, muitos casos de produtos magistrais fabricados fora do padrão mínimo de qualidade têm sido relatados no Brasil. Neste trabalho, a qualidade das cápsulas magistrais de fluconazol 150 mg foi avaliada e os resultados foram comparados com os valores recomendados pela Farmacopeia Brasileira. Os resultados sugerem que é possível manipular produtos que satisfaçam as especificações farmacopeicas, mas estes ainda mostram que há farmácias magistrais onde o controle de qualidade é deficiente ou inexistente. O fluconazol é um fármaco importante no tratamento de infecções fúngicas. Seu uso como forma farmacêutica manipulada sem elevados padrões de qualidade é fortemente relacionado com a falha terapêutica e intoxicações, assim como o surgimento de microorganismos resistentes. Portanto, a necessidade de melhoria dos processos nas farmácias magistrais se torna mais enfático. Existem métodos validados que podem ser utilizados com sucesso para a análise de rotina de controle de qualidade e que podem ser implementados por qualquer farmácia de manipulação...

The quality control of drugs has an important role in public health, in ensuring the efficacy and safety of medicines. In the public health system, compounding pharmacies play a vital part. They provide medicines tailored to the individual patient, for example dermatological products and specific doses for children. Unfortunately, many cases of compounded products falling below the minimum quality standard have been reported in Brazil. In this study, the quality of compounded 150 mg fluconazole capsules was assessed and the results were compared with values stipulated in the Brazilian pharmacopoeia. The results suggest that, while it is certainly possible to prepare products meeting pharmacopoeial specifications, there are pharmacies where the quality control is deficient or nonexistent. Fluconazole is an important drug in combatting fungal infections. The use of fluconazole in dosage forms manufactured without high standards of quality control is strongly linked to treatment failure and cases of intoxication, as well as the emergence of resistant microorganisms. This highlights the urgent need for process improvement in compounding pharmacies. There are validated methods that can be successfully employed for routine quality control analysis that can be implemented by any compounding pharmacy...