To resolve the growing problem of drug resistance in the treatment of bacterial and fungal pathogens, specific cellular targets and pathways can be used as targets for new antimicrobial agents. Endogenous riboflavin biosynthesis is a conserved pathway that exists in most bacteria and fungi. In this review, the roles of endogenous and exogenous riboflavin in infectious disease as well as several antibacterial agents, which act as analogues of the riboflavin biosynthesis pathway, are summarized. In addition, the effects of exogenous riboflavin on immune cells, cytokines, and heat shock proteins are described. Moreover, the immune response of endogenous riboflavin metabolites in infectious diseases, recognized by MHC-related protein-1, and then presented to mucosal associated invariant T cells, is highlighted. This information will provide a strategy to identify novel drug targets as well as highlight the possible clinical use of riboflavin.
Cryptococcus neoformans is an invasive fungus that causes both acute and chronic infections, especially in immunocompromised patients. Owing to the increase in the prevalence of drug-resistant pathogenic fungi and the limitations of current treatment strategies, drug repositioning has become a feasible strategy to accelerate the development of new drugs. In this study, the minimum inhibitory concentration of vitamin D3 (VD3) against C. neoformans was found to be 0.4 mg/mL by broth microdilution assay. The antifungal activities of VD3 were further verified by solid dilution assays and “time-kill” curves. The results showed that VD3 reduced fungal cell adhesion and hydrophobicity and inhibited biofilm formation at various developmental stages, as confirmed by crystal violet staining and the 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide assay. Fluorescence staining of cellular components and a stress susceptibility assay indicated that VD3 compromised cell integrity. Reverse transcription quantitative PCR demonstrated that VD3 treatment upregulated the expression of fungal genes related to cell wall synthesis (i.e., CDA3, CHS3, FKS1, and AGS1). Moreover, VD3 enhanced cell membrane permeability and caused the accumulation of intracellular reactive oxygen species. Finally, VD3 significantly reduced the tissue fungal burden and prolonged the survival of Galleria mellonella larvae infected with C. neoformans. These results showed that VD3 could exert significant antifungal activities both in vitro and in vivo, demonstrating its potential application in the treatment of cryptococcal infections.
Candida
species are common pathogens in fungal infections, causing mucosal infection and invasive infection in immunodeficient patients. Given the limited classes of drugs and resistance to these drugs, new antifungal agents need to be developed.
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