piperidines and Candidiasis

Candida albicans is a member of pathogens with potential drug resistance threat that needs novel chemotherapeutic strategies. Considering the multifarious biological activities including bioenhancer activity, anti-Candida potential of piperine was evaluated against planktonic/biofilm and hyphal growth of C. albicans alone or in combination as a synergistic agent with fluconazole. Piperine inhibits planktonic growth at or less than 15 μg/ml, hyphae induction at 5 μg/ml concentration, and exhibits stage-dependent activity against biofilm growth of a fluconazole-resistant strain of C. albicans (ATCC10231). Though piperine couldn't kill inoculum completely at minimum inhibitory concentration (MIC), it is fungicidal at higher concentrations, as shown in apoptosis assay. FIC index values indicate that piperine exhibits excellent synergistic activity with fluconazole against planktonic (0.123) and biofilm (0.215) growth of an FLC resistant strain. Mode of anti-Candida activity was studied by identifying piperine responsive proteins wherein the abundance of 25 proteins involved in stress response, signal transduction and cell cycle were modulated (22 up and 3 down-regulated) significantly in response to piperine (MIC50). Modulation of the proteins involved suggests that piperine affects membrane integrity leading to oxidative stress followed by cell cycle arrest and apoptosis in C. albicans. Flow cytometry-based mitochondrial membrane potential (MMP), cell cycle and apoptosis assay, as well as real-time quantitative polymerase chain reaction analysis of selected genes, confirms piperine induced oxidative stress (TRR1), cell cycle arrest and apoptosis (CaMCA1). Based on our results, we conclude that piperine inhibits planktonic and difficult-to treat-biofilm growth of C. albicans by affecting membrane integrity thereby inducing oxidative stress and apoptosis.. Piperine inhibit Candida albicans growth (planktonic and biofilm) significantly in our study. Piperine exhibits excellent synergistic potential with fluconazole The proteome analysis suggests that piperine induced membrane damage leads to oxidative stress followed by cell cycle arrest and apoptosis.

Topics: Alkaloids; Antifungal Agents; Apoptosis; Benzodioxoles; Biofilms; Candida albicans; Candidiasis; Drug Resistance, Fungal; Drug Synergism; Fluconazole; Hyphae; Microbial Sensitivity Tests; Oxidative Stress; Piperidines; Plant Extracts; Polyunsaturated Alkamides

Tofacitinib (CP-690550), an oral Janus kinase inhibitor, has shown significant efficacy in the treatment of rheumatoid arthritis through blocking the signaling pathways of pro-inflammatory cytokines. However, recent evidence suggests that long-term tofacitinib treatment is associated with increased risk of infection (e.g. tuberculosis) in patients. In the present study, we illustrate that tofacitinib administration significantly reduced the survival rate of mice given lethal or sub-lethal dose challenge with Candida albicans. This was related to the ability of tofacitinib to reverse TNFα- and IFNγ-enhanced candidacidal activity of murine polymorph nuclear cells (PMNs) and also to suppress chemokine CXCL5 expression and PMN infiltration in the infected tissues of mice. More importantly, tofacitinib significantly antagonized the ability of TNFα, IFNγ and GM-CSF to boost human PMNs in phagocytosis and direct killing of C. albicans in vitro. It also down-regulated reactive oxygen production and neutrophil extracellular trap formation by human PMNs stimulated with yeast-derived β-glucans in the presence of TNFα, IFNγ or GM-CSF. Our data emphasizes a significantly increased risk for opportunistic fungal infection associated long-term tofacitinib treatment in humans, likely through antagonizing the PMN-boosting effect of pro-inflammatory cytokines.

Topics: Administration, Oral; Adult; Animals; Arthritis, Rheumatoid; Candida albicans; Candidiasis; Disease Susceptibility; Female; Humans; Mice, Inbred BALB C; Neutrophil Activation; Neutrophils; Phagocytosis; Piperidines; Pyrimidines; Pyrroles; Risk Factors

Aminopiperidine derivatives, Compound 1a and 1b, are novel small molecules that inhibit C-14 reduction catalyzed by Erg24p in ergosterol synthesis of Candida albicans. We evaluated the properties of the in vitro and in vivo activities of these compounds against pathogenic fungi and compared their activities with those of fluconazole. Compound 1a and 1b exhibited potent in vitro activities against clinically important fungi such as Candida species, including both of fluconazole-resistant strains of C. albicans and non-albicans Candida, Aspergillus fumigatus, and Cryptococcus neoformans. Against C. albicans, its mode of action was fungistatic. Furthermore, orally administered Compound 1b clearly prolonged the survival of infected mice in systemic lethal infection caused by C. albicans. These results suggest that aminopiperidine derivative is a promising lead compound for an orally available novel antifungal drug with a broad spectrum.

Topics: Animals; Antifungal Agents; Candida albicans; Candidiasis; Ergosterol; Female; Fluconazole; Fungi; Inhibitory Concentration 50; Kaplan-Meier Estimate; Mice; Microbial Sensitivity Tests; Molecular Structure; Piperidines

The protective effect of an interferon inducer with a low molecular weight, 9-methylstreptimidone (9-MS), against Candida albicans infection in mice was investigated. The antibiotic was effective only when given prophylactically. When administered in such a manner, the growth of C. albicans in the kidneys and brain was inhibited at the initial stage of infection. The growth of C. albicans was not inhibited by the antibiotic in vitro, and no antifungal effect was obtained in a preparation containing induced interferon. These results suggest that the antifungal action of 9-methylstreptimidone in mice might be manifested not by direct antifungal activity but rather by a host-mediated activity that excludes interferon-inducing capability.

Topics: Animals; Candida albicans; Candidiasis; Female; Interferon Inducers; Interferons; Mice; Piperidines; Piperidones; Time Factors

Topics: Abscess; Acute Kidney Injury; Agranulocytosis; Brain; Brain Abscess; Candidiasis; Humans; Medical Records; Piperidines; Tartrates