There has been a sharp rise in the occurrence of Candida infections and associated mortality over the last few years, due to the growing body of immunocompromised population. Limited number of currently available antifungal agents, undesirable side effects and toxicity, as well as emergence of resistant strains pose a considerable clinical challenge for the treatment of candidiasis. Therefore, molecules that derived from natural sources exhibiting considerable antifungal properties are a promising source for the development of novel anti-candidal therapy. Phenolic compounds isolated from natural sources possess antifungal properties of interest. Particularly, phenolic acids have shown promising in vitro and in vivo activity against Candida species. However, studies on their mechanism of action alone or in synergism with known antifungals are still scarce. This review attempts to discuss the potential use, proposed mechanisms of action and limitations of the phenolic acids in anti-candidal therapy.
Candida albicans, a major opportunistic fungal pathogen, is frequently found together with Streptococcus mutans in dental biofilms associated with severe childhood caries (tooth decay), a prevalent pediatric oral disease. However, the impact of this cross-kingdom relationship on C. albicans remains largely uncharacterized. Here, we employed a novel quantitative proteomics approach in conjunction with transcriptomic profiling to unravel molecular pathways of C. albicans when cocultured with S. mutans in mixed biofilms. RNA sequencing and iTRAQ (isobaric tags for relative and absolute quantitation)-based quantitative proteomics revealed that C. albicans genes and proteins associated with carbohydrate metabolism were significantly enhanced, including sugar transport, aerobic respiration, pyruvate breakdown, and the glyoxylate cycle. Other C. albicans genes and proteins directly and indirectly related to cell morphogenesis and cell wall components such as mannan and glucan were also upregulated, indicating enhanced fungal activity in mixed-species biofilm. Further analyses revealed that S. mutans-derived exoenzyme glucosyltransferase B (GtfB), which binds to the fungal cell surface to promote coadhesion, can break down sucrose into glucose and fructose that can be readily metabolized by C. albicans, enhancing growth and acid production. Altogether, we identified key pathways used by C. albicans in the mixed biofilm, indicating an active fungal role in the sugar metabolism and environmental acidification (key virulence traits associated with caries onset) when interacting with S. mutans, and a new cross-feeding mechanism mediated by GtfB that enhances C. albicans carbohydrate utilization. In addition, we demonstrate that comprehensive transcriptomics and quantitative proteomics can be powerful tools to study microbial contributions which remain underexplored in cross-kingdom biofilms.
Streptococcus mutans is a biofilm-forming oral pathogen commonly associated with dental caries. Clinical studies have shown that S. mutans is often detected with Candida albicans in early childhood caries. Although the C. albicans presence has been shown to enhance bacterial accumulation in biofilms, the influence of S. mutans on fungal biology in this mixed-species relationship remains largely uncharacterized. Therefore, we aimed to investigate how the presence of S. mutans influences C. albicans biofilm development and coexistence. Using a newly established haploid biofilm model of C. albicans, we found that S. mutans augmented haploid C. albicans accumulation in mixed-species biofilms. Similarly, diploid C. albicans also showed enhanced biofilm formation in the presence of S. mutans. Surprisingly, the presence of S. mutans restored the biofilm-forming ability of C. albicans bcr1Δ mutant and bcr1Δ/Δ mutant, which is known to be severely defective in biofilm formation when grown as single species. Moreover, C. albicans hyphal growth factor HWP1 as well as ALS1 and ALS3, which are also involved in fungal biofilm formation, were upregulated in the presence of S. mutans. Subsequently, we found that S. mutans-derived glucosyltransferase B (GtfB) itself can promote C. albicans biofilm development. Interestingly, GtfB was able to increase the expression of HWP1, ALS1, and ALS3 genes in the C. albicans diploid wild-type SC5314 and bcr1Δ/Δ, leading to enhanced fungal biofilms. Hence, the present study demonstrates that a bacterial exoenzyme (GtfB) augments the C. albicans counterpart in mixed-species biofilms through a BCR1-independent mechanism. This novel finding may explain the mutualistic role of S. mutans and C. albicans in cariogenic biofilms.
The time needed for the osseointegration of titanium implants is deemed too long. Moreover, the bacterial colonization of their surfaces is a major cause of failure. Graphene can overcome these issues but its wet transfer onto substrates employs hazardous chemicals limiting the clinical applications. Alternatively, dry transfer technique has been developed, but the biological properties of this technique remain unexplored. Here, a dry transfer technique based on a hot-pressing method allowed to coat titanium substrates with high-quality graphene and coverage area >90% with a single transfer. The graphene-coated titanium is cytocompatible, did not induce cell membrane damage, induced human osteoblast maturation (gene and protein level), and increased the deposition of mineralized matrix compared to titanium alone. Moreover, graphene decreased the formation of biofilms from Streptococcus mutans, Enterococcus faecalis and even from whole saliva on titanium without killing the bacteria. These findings confirm that coating of titanium with graphene via a dry transfer technique is a promising strategy to improve osseointegration and prevent biofilm formation on implants and devices.
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