Although modern lifestyle has eased the quality of human life, this lifestyle's related patterns have imparted negative effects on health to acquire multiple diseases. Many synthetic drugs are invented during the last millennium but most if not all of them possess several side effects and proved to be costly. Convincing evidences have established the premise that the phytotherapeutic potential of natural compounds and need of search for novel drugs from natural sources are of high priority. Phenolic acids (PAs) are a class of secondary metabolites spread throughout the plant kingdom and generally involved in plethora of cellular processes involved in plant growth and reproduction and also produced as defense mechanism to sustain various environmental stresses. Extensive research on PAs strongly suggests that consumption of these compounds hold promise to offer protection against various ailments in humans. This paper focuses on the naturally derived PAs and summarizes the action mechanisms of these compounds during disease conditions. Based on the available information in the literature, it is suggested that use of PAs as drugs is very promising; however more research and clinical trials are necessary before these bioactive molecules can be made for treatment. Finally this review provides greater awareness of the promise that natural PAs hold for use in the disease prevention and therapy.

Recently the high incidence of worldwide Candida infections has substantially increased. The growing problem about toxicity of antifungal drugs and multidrug resistance aggravates the need for the development of new effective strategies. Natural compounds in this context represent promising alternatives having potential to be exploited for improving human health. The present study was therefore designed to evaluate the antifungal effect of a naturally occurring phenolic, octyl gallate (OG), on Candida albicans and to investigate the underlying mechanisms involved. We demonstrated that OG at 25 μg/ml could effectively inhibit C. albicans. Mechanistic insights revealed that OG affects mitochondrial functioning as Candida cells exposed to OG did not grow on non-fermentable carbon sources. Dysfunctional mitochondria triggered generation of reactive oxygen species (ROS), which led to membrane damage mediated by lipid peroxidation. We explored that OG inhibited glucose-induced reduction in external pH and causes decrement in ergosterol levels by 45%. Furthermore, OG impedes the metabolic flexibility of C. albicans by inhibiting the glyoxylate enzyme isocitrate lyase, which was also confirmed by docking analysis. Additionally, OG affected virulence traits such as morphological transition and cell adherence. Furthermore, we depicted that OG not only prevented biofilm formation but eliminates the preformed biofilms. In vivo studies with Caenorhabditis elegans nematode model confirmed that OG could enhance the survival of C. elegans after infection with Candida. Toxicity assay using red blood cells showed only 27.5% haemolytic activity. Taken together, OG is a potent inhibitor of C. albicans that warrants further structural optimization and pharmacological investigations.

Introduction: Citronellal (Cit) possesses antifungal activity and has possible implications for reactive oxygen species (ROS) generation in Candida albicans. In this study, the effects of Cit on ROS generation and the mechanisms by which Cit exerts anti-Candida effects were examined. Methods: A 2′,7′-dichlorodihydrofluorescein diacetate assay was used to assess oxidative damage. Cell necrosis was determined by flow cytometry after FITC-Annexin V staining. Mitochondrial function was studied based on mitochondrial potential, metabolic activity (MTT assay), and phenotypic susceptibility on a non-fermentable carbon source. Membrane intactness and DNA damage were estimated by a propidium iodide (PI) uptake assay and 4',6-diamidino-2-phenylindole (DAPI) staining. Results: ROS generation was enhanced in response to Cit, leading to necrosis (2%). Additional hallmarks of cell death in response to Cit, such as mitochondrial membrane depolarization and DNA damage, were also observed. Cit treatment resulted in dysfunctional mitochondria, as evidenced by poor labeling with the mitochondrial membrane potential-sensitive probe rhodamine B, reduced metabolic activity (61.5%), and inhibited growth on a non-fermentable carbon source. Furthermore, Cit induced DNA damage based on DAPI staining. These phenotypes were reinforced by RT-PCR showing differences in gene expression (30-60%) between control and Cit-treated cells. Finally, PI uptake in the presence of sodium azide confirmed non-intact membranes and suggested that Cit activity is independent of the energy status of the cell. Conclusions: Cit possesses dual anticandidal mechanisms, including membrane-disruptive and oxidative damage. Taken together, our data demonstrated that cit could be used as a prominent antifungal drug.

Significance of methylene blue (MB) in photodynamic therapy against microbes is well established. Previously, we have reported the antifungal potential of MB against Candida albicans. The present study attempts to identify additional antimicrobial effect of MB against another prevalent human pathogen, Mycobacterium tuberculosis (MTB). We explored that MB is efficiently inhibiting the growth of Mycobacterium at 15.62 μg/ml albeit in bacteriostatic manner similar to its fungistatic nature. We uncovered additional cell surface phenotypes (colony morphology and cell sedimentation rate) which were impaired only in Mycobacterium. Mechanistic insights revealed that MB causes energy dependent membrane perturbation in both C. albicans and Mycobacterium. We also confirmed that MB leads to enhanced reactive oxygen species generation in both organisms that could be reversed upon antioxidant supplementation; however, DNA damage could only be observed in Mycobacterium. We provided evidence that although biofilm formation was disrupted in both organisms, cell adherence to human epithelial cells was inhibited only in Mycobacterium. Lastly, RT-PCR results showed good correlation with the biochemical assay. Together, apart from the well-established role of MB in photodynamic therapy, this study provides insights into the distinct antimicrobial mode of actions in two significant human pathogens, Candida and Mycobacterium, which can be extrapolated to improve our understanding of finding novel therapeutic options.

No abstract

Background: Considering the emergence of multidrug resistance (MDR) in prevalent human fungal pathogen, Candida albicans, there is parallel spurt in development of novel strategies aimed to disrupt MDR. Compounds from natural resources could be exploited as efficient antifungal drugs owing to their structural diversity, cost effectiveness and negligible side effects. Objective: The present study elucidates the antifungal mechanisms of Vanillin (Van), a natural food flavoring agent against Candida albicans. Methods: Antifungal activities were assessed by broth microdilution and spot assays. Membrane and cell wall perturbations were studied by PI uptake, electron microscopy, plasma membrane H+ extrusion activity and estimation of ergosterol and chitin contents. Mitochondrial functioning was studied by growth on non-fermentable carbon sources, rhodamine B labeling and using retrograde signaling mutants. Gene expressions were validated by semi-quantitative RT-PCR. Results: We observed that the antifungal activity of Van was not only limited to clinical isolates of C. albicans but also against non-albicans species of Candida. Mechanistic insights revealed effect of Van on cell surface integrity as evident from hypersensitivity against membrane perturbing agent SDS, depleted ergosterol levels, transmission electron micrographs and diminished plasma membrane H+ extrusion activity. In addition, spot assays with cell wall perturbing agents, scanning electron micrographs, delayed sedimentation rate and lower chitin content further substantiate cell wall damage by Van. Furthermore, Van treated cells underwent mitochondrial dysfunctioning via impaired retrograde signaling leading to abrogated iron homeostasis and DNA damage. All the perturbed phenotypes were also validated by RT-PCR depicting differential regulation of genes (NPC2, KRE62, FTR2 and CSM3) in response to Van. Conclusion: Together, our results suggested that Van is promising antifungal agent that may be advocated for further investigation in therapeutic strategies to treat Candida infections.

No abstract

No abstract