Antifungal Activity of Mefloquine Against Candida albicans Growth and Virulence Factors: Insights Into Mode of Action.

The antimalarial drug Mefloquine has demonstrated antifungal activity against growth and virulence factors of Candida albicans. The current study focused on the identification of Mefloquine's mode of action in C. albicans by performing cell susceptibility assay, biofilm assay, live and dead assay, propidium iodide uptake assay, ergosterol quantification assay, cell cycle study, and gene expression studies by RT-PCR. Mefloquine inhibited the virulence factors in C. albicans, such as germ tube formation and biofilm formation at 0.125 and 1 mg/ml, respectively. Mefloquine-treated cells showed a decrease in the quantity of ergosterol content of cell membrane in a concentration-dependent manner. Mefloquine (0.25 mg/ml) arrested C. albicans cells at the G2/M phase and S phase of the cell cycle thereby preventing the progression of the normal yeast cell cycle. ROS level was measured to find out oxidative stress in C. albicans in the presence of mefloquine. The study revealed that, mefloquine was found to enhance the ROS level and subsequently oxidative stress. Gene expression studies revealed that mefloquine treatment upregulates the expressions of SOD1, SOD2, and CAT1 genes in C. albicans. In vivo, the antifungal efficacy of mefloquine was confirmed in mice for systemic candidiasis and it was found that there was a decrease in the pathogenesis of C. albicans after the treatment of mefloquine in mice. In conclusion, mefloquine can be used as a repurposed drug as an alternative drug against Candidiasis.

MIG1, TUP1 and NRG1 mediated yeast to hyphal morphogenesis inhibition in Candida albicans by ganciclovir.

Candida albicans is a polymorphic human fungal pathogen and the prime etiological agent responsible for candidiasis. The main two aspects of C. albicans virulence that have been suggested are yeast-to-hyphal (Y-H) morphological transitions and biofilm development. Anti-fungal agents targeting these virulence attributes enhances the antifungal drug development process. Repositioning with other non-fungal drugs offered a one of the new strategies and a potential alternative option to counter the urgent need for antifungal drug development. In the current study, an antiviral drug ganciclovir was screened as an antifungal agent against ATCC 90028, 10231 and clinical isolate (C1). Ganciclovir at 0.5 mg/ml concentration reduced 50% hyphal development on a silicon-based urinary catheter and was visualized using scanning electron microscopy. Ganciclovir reduced ergosterol biosynthesis in both strains and C1 isolate of C. albicans in a concentration-dependent manner. Additionally, a gene expression profile study showed that ganciclovir treatment resulted in upregulation of hyphal-specific repressors MIG1, TUP1, and NRG1 in C. albicans. Additionally, an in vivo study on the Bombyx mori silkworm model further evidenced the virulence inhibitory ability of ganciclovir (0.5 mg/ml) against C. albicans. This is the first report that explore the novel anti-morphogenic activities of ganciclovir against the pathogenic C. albicans strains, along with clinical isolates. Further, ganciclovir may be considered for therapeutic purpose after combinations with standard antifungal agents.

Butyl isothiocyanate exhibits antifungal and anti-biofilm activity against Candida albicans by targeting cell membrane integrity, cell cycle progression and oxidative stress.

The prevalence of Candida albicans infection has increased during the past few years, which contributes to the need for new, effective treatments due to the increasing concerns regarding antifungal drug toxicity and multidrug resistance. Butyl isothiocyanate (butylITC) is a glucosinolate derivative, and has shown a significant antifungal effect contrary to Candida albicans. Additionally, how butylITC affects the virulence traits of C. albicans and molecular mode of actions are not well known. Present study shows that at 17.36 mM concentration butylITC inhibit planktonic growth. butylITC initially slowed the hyphal transition at 0.542 mM concentration. butylITC hampered biofilm development, and inhibits biofilm formation at 17.36 mM concentration which was analysed using metabolic assay (XTT assay) and Scanning Electron Microscopy (SEM). In addition, it was noted that butylITC inhibits ergosterol biosynthesis. The permeability of cell membranes was enhanced by butylITC treatment. Moreover, butylITC arrests cells at S-phase and induces intracellular Reactive Oxygen Species (ROS) accumulation in C. albicans. The results suggest that butylITC may have a dual mode of action, inhibit virulence factors and modulate cellular processes like inhibit ergosterol biosynthesis, cell cycle arrest, induces ROS production which leads to cell death in C. albicans.

Hydroxychloroquine an Antimalarial Drug, Exhibits Potent Antifungal Efficacy Against Candida albicans Through Multitargeting.

Candida albicans is the primary etiological agent associated with candidiasis in humans. Unrestricted growth of C. albicans can progress to systemic infections in the worst situation. This study investigates the antifungal activity of Hydroxychloroquine (HCQ) and mode of action against C. albicans. HCQ inhibited the planktonic growth and yeast to hyphal form morphogenesis of C. albicans significantly at 0.5 mg/ml concentration. The minimum inhibitory concentrations (MIC50) of HCQ for C. albicans adhesion and biofilm formation on the polystyrene surface was at 2 mg/ml and 4 mg/ml respectively. Various methods, such as scanning electron microscopy, exploration of the ergosterol biosynthesis pathway, cell cycle analysis, and assessment of S oxygen species (ROS) generation, were employed to investigate HCQ exerting its antifungal effects. HCQ was observed to reduce ergosterol levels in the cell membranes of C. albicans in a dose-dependent manner. Furthermore, HCQ treatment caused a substantial arrest of the C. albicans cell cycle at the G0/G1 phase, which impeded normal cell growth. Gene expression analysis revealed upregulation of SOD2, SOD1, and CAT1 genes after HCQ treatment, while genes like HWP1, RAS1, TEC1, and CDC 35 were downregulated. The study also assessed the in vivo efficacy of HCQ in a mice model, revealing a reduction in the pathogenicity of C. albicans after HCQ treatment. These results indicate that HCQ holds for the development of novel antifungal therapies.

Development and In-Vitro Evaluation of Eugenol-Based Nanostructured Lipid Carriers for Effectual Topical Treatment Against C. albicans.

The main objective of the experiment is to develop and evaluate hydrogel-bearing nanostructured lipid carriers (NLCs) loaded with ketoconazole (KTZ) for the effective treatment of candidiasis. The eugenol was used as a liquid lipid (excipient) for the development of KTZ-loaded NLCs and was explored for anti-fungal effect. The production of NLCs involves high energy processes to generate spherical, uniform particles, having a higher percentage of entrapment efficiency (%EE) for KTZ with 89.83 ± 2.31 %. The data from differential scanning calorimeter (DSC), powder x-ray diffraction (PXRD), and attenuated total reflectance (ATR) demonstrated the KTZ dispersion in NLCs. The NLCs loaded hydrogel possessed optimum spreadability and exhibited shear thinning behavior, indicating the ease of application of the final formulation. The 6.41-fold higher transdermal flux (Jss) was governed for KTZ from KTZ-NLC than coarse-KTZ, which explains the usefulness of NLCs. The KTZ-NLCs exhibited significant 2.58 and 6.35-fold higher retention in the stratum corneum and viable epidermis of the skin. The cell cytotoxicity studies using human dermal fibroblast cell (HDFS) lines depicted the usefulness of NLCs in reducing cell toxicities for KTZ. The KTZ-NLCs were found to inhibit planktonic growth and hyphal transition and showed a larger zone of inhibition against C. albicans strains with a MIC-50 value of 0.39 µg/mL. The antibiofilm activity of KTZ-NLCs at lower concentrations, in contrast to plain KTZ, explained the interaction of developed NLCs with fungal membranes. The overall results depicted the effectiveness of the loading KTZ in the lipid matrix to achieve antifungal activity against C. albicans.

Ethyl Isothiocyanate as a Novel Antifungal Agent Against Candida albicans.

In the recent years, occurrence of candidiasis has increased drastically which leads to significant mortality and morbidity mainly in immune compromised patients. Glucosinolate (GLS) derivatives are reported to have antifungal activities. Ethyl isothiocyanate (EITC) and its antifungal activity and mechanism of action is still unclear against Candida albicans. The present work was designed to get a mechanistic insight in to the anti-Candida efficacy of EITC through in vitro and in vivo studies. EITC inhibited C. albicans planktonic growth at 0.5 mg/ml and virulence factors like yeast to hyphal form morphogenesis (0.0312 mg/ml), adhesion to polystyrene surface (0.0312 mg/ml) and biofilm formation (developing biofilm at 2 mg/ml and mature biofilm at 0.5 mg/ml) effectively. EITC blocked ergosterol biosynthesis and arrested C. albicans cells at S-phase. EITC caused ROS-dependent cellular death and nuclear or DNA fragmentation. EITC at 0.0312 mg/ml concentration regulated the expression of genes involved in the signal transduction pathway and inhibited yeast to hyphal form morphogenesis by upregulating TUP1, MIG1, and NRG1 by 3.10, 5.84 and 2.64-fold, respectively and downregulating PDE2 and CEK1 genes by 15.38 and 2.10-fold, respectively. EITC has showed haemolytic activity at 0.5 mg/ml concentration. In vivo study in silk worm model showed that EITC has toxicity to C. albicans at 0.5 mg/ml concentration. Thus, from present study we conclude that EITC has antifungal activity and to reduce its MIC and toxicity, combination study with other antifungal drugs need to be done. EITC and its combinations might be used as alternative therapeutics for the prevention and treatment of C. albicans infections.

Design, Docking, Characterisation, and Synthesis of Pyrimidine Derivatives for Antidepressant Activity.

BACKGROUND: According to the report, in 2022, the prevalence rate of depression in India was 4.50%, and the cases stood at 56,675,969. The development of antidepressant agents has reduced the number of depressant and suicidal cases. Many researchers have found that pyrimidine possesses antidepressant activity. With this background, we thought of synthesizing pyrimidine derivatives. OBJECTIVE: The objective of this study is to carry out molecular docking, synthesis, characterization, and evaluation of 2-((4,6-diphenylpyrimidin-2-yl)oxy)-N-phenylacetamide derivatives (17-26) as in vivo antidepressant agent. METHOD: The designed compounds were checked for their activity using Molegro virtual docker (MVD) and were further synthesized. Benzaldehyde reacted with acetophenone to give compound (3), which gave compound (4) upon reaction with urea. In another reaction, substituted anilines (5) were reacted with chloroacetyl chloride (6) to yield compounds (7-16), which upon further reaction with compound (4) yielded the final derivatives (17-26). The synthesized compounds were characterized by spectral analysis and checked for their antidepressant activity. RESULT: The MolDock scores of the derivatives ranged from -147.097 to -182.095, whereas of active ligand IXX_801 was -115.566. All the synthesized pyrimidine derivatives showed better affinity towards the Cryo-EM structure of the wild-type human serotonin transporter complexed with vilazodone, imipramine, and 15B8 Fab protein (PDB ID: 7LWD) as compared to standard drug clomipramine (-101.064). All the synthesized derivatives were screened for antidepressant activity at a 100mg/kg dose level compared to the standard clomipramine HCl at a dose level of 20mg/kg. Among all the synthesized derivatives, compound 24 showed the most potent antidepressant activity, and Compound 20 showed moderate antidepressant activity, which reduced the duration of immobility times to 35.42% and 31.97% at 100mg/kg dose level when compared to the control, respectively. CONCLUSION: Compound 24 showed the highest MolDock score as well as found to be the most potent antidepressant agent.

Isothiocyanates as potential antifungal agents: a mini-review.

Cruciferous vegetables and mustard oil are rich in the glucosinolate group of molecules. Isothiocyanates are an important group of glucosinolate derivatives. These derivatives have various bioactive properties, including antioxidant, antibacterial, anticarcinogenic, antifungal, antiparasitic, herbicidal and antimutagenic activity. Previous studies indicate that regular intake of such vegetables may considerably reduce the incidence of various types of cancer. These studies have inspired studies where the bioactive agents of these plants have been isolated and explored for their therapeutic applications. The use of these bioactive compounds as antifungals could be a new therapeutic approach against human pathogenic fungi. Isothiocyanates have been studied for their antifungal activity and have the potential to be used for antifungal therapy.

Vegetables like cabbage, cauliflower and broccoli have a distinct flavor because of chemicals called glucosinolates. Whenever we cut and eat these vegetables, glucosinolates are broken down into isothiocyanates. Glucosinolates and isothiocyanates have health benefits because they stop the growth of bacteria, parasites and fungi that cause disease, such as Candida albicans. They may also prevent cancer, as regularly eating these vegetables has been shown to reduce the development of some types of cancer in humans. Investigation is needed to explore how glucosinolates and isothiocyanates could be used to treat fungal infections.

Adherence to behavioural intervention in RCT study by the women experiencing domestic violence and attending ANC in a public hospital in India-an analysis.

Background: The paper aims to identify the factors for effective implementation and adherence to the behavioural intervention package by women experiencing domestic violence (DV) and attending ANC in a public hospital. Methods: A qualitative study was undertaken with 211 pregnant women experiencing DV and attending antenatal care (ANC) at the LN Hospital, New Delhi. The intervention was given to women recruited under the RCT study. The narratives were analysed under two broad themes, impeding and facilitating factors, with nine sub-themes. Findings: Impeding factors are external factors generated by the structural interaction of the participants, whereas facilitating factors are supplied internally in the trial to eliminate the influence of impeding factors and singulate the factors under study. Our results show that despite the plethora of impeding factors (nine), the overall sum impact of impeding factors falls short of the positive impact of facilitating factors (nine), which were minor adjustments but reinforce participation in the trial and adherence with 97% follow-up rates. Interpretation: Our study findings are expected to reset the treatment protocol, which entails converting impeding factors into facilitating factors for appropriate adherence and compliance and adequate access and utilization of public services. The sensitization of healthcare providers to the impact of the quality of human interaction on the patient and its impact on the uptake of healthcare services and adherence is needed, particularly in the public hospitals of India. Funding: Funds received for the research are from the Indian Council of Medical Research (ICMR), New Delhi, Government of India.

Antifungal activity of Allyl isothiocyanate by targeting signal transduction pathway, ergosterol biosynthesis, and cell cycle in Candida albicans.

Background and Purpose: In recent years, the inclusion of Candida albicans on the list of infections that pose a threat due to drug resistance has urged researchers to look into cutting-edge and effective antifungal medications. In this regard, the current study investigated the probable mode of action of allyl isothiocyanate (AITC) against Candida albicans. Materials and Methods: In this study, planktonic assay, germ tube inhibition assay, adhesion, and biofilm formation assay were performed to check the growth and virulence factors. Furthermore, ergosterol assay, reactive oxygen production analysis, cell cycle analysis, and quantitative real-time polymerase chain reaction analysis were performed with the aim of finding the mode of action. A biomedical model organism, like a silkworm, was used in an in vivo study to demonstrate AITC anti-infective ability against C. albicans infection. Results: Allyl isothiocyanate completely inhibited ergosterol biosynthesis in C. albicans at 0.125 mg/ml. Allyl isothiocyanate produces reactive oxygen species in both planktonic and biofilm cells of C. albicans. At 0.125 mg/ml concentration, AITC arrested cells at the G2/M phase of the cell cycle, which may induce apoptosis in C. albicans. In quantitative real-time polymerase chain reaction analysis, it was found that AITC inhibited virulence factors, like germ tube formation, at 0.125 mg/ml concentration by downregulation of PDE2, CEK1, TEC1 by 2.54-, 1.91-, and 1.04-fold change, respectively, and upregulation of MIG1, NRG1, and TUP1 by 9.22-, 3.35-, and 7.80-fold change, respectively. The in vivo study showed that AITC treatment successfully protected silkworms against C. albicans infections and increased their survival rate by preventing internal colonization by C. albicans. Conclusion: In vitro and in vivo studies revealed that AITC can be an alternative therapeutic option for the treatment of C. albicans infection.

Randomized, controlled clinical trial to evaluate efficacy of sticky bone and concentrated growth factor in the management of intrabony defects: 12 months follow-up study.

Background: Platelet derivatives are enriched growth factors that ameliorate various cellular processes in regeneration. The present clinical trial aimed to evaluate and compare the effects of sticky bone and concentrated growth factors (CGFs) in the treatment of intrabony osseous defects by cone-beam computed tomography (CBCT). Materials and Methods: The study included 20 patients having 40 intrabony defects. 20 sites each were included in both test group (Sticky bone) and Control group (CGF alone). The clinical parameters including probing pocket depth (PPD) and clinical attachment level (CAL) were assessed at baseline and 6 and 12 months posttherapy. The radiographic parameters including the depth, mesiodistal (MD), and the buccolingual (BL) width of the defect to assess the amount of bone fill were examined at baseline and after 12 months using CBCT. Results: Twelve months posttherapy clinical results indicated a significant reduction of PPD and gain in CAL in both the study groups. Similar observations were recorded with CBCT radiographic parameters where the intrabony defect depth and MD defect width for the test group and control group significantly reduced after 12 months' posttherapy (P < 0.0001). However, no significant reduction in BL defect width was observed in control group (P = 0.577) in contrast to the test group (P = 0.028) after 12 months' posttherapy. Conclusion: Intrabony defects treated with sticky bone showed improved clinical and radiographic parameters indicative of enhanced periodontal regeneration as compared to CGF alone treated sites.

Domestic Violence during pregnancy as risk factors for stress and depression: The experience of women attending ANC at atertiary care hospital in India.

Domestic Violence (DV) during the antenatal period has major effects on the mother and pregnancy outcome and is associated with stress and mental health problems. The paper aims to examine the association of DV with stress and depression (S&D) during the first trimester of pregnancy attending antenatal care (ANC) at the Lok Nayak (LN) hospital, a tertiary healthcare hospital in New Delhi, India and address the response of the women. A mixed method was used to gain an in-depth understanding of the participants. A total of 921 women were screened from November 2018 to March 2020 using standard tools for the presence of incidents of DV and S&D. 517 pregnant women with up to 20 weeks of pregnancy who met the inclusion criteria and came to receive ANC at the facility were considered. The prevalence of DV in various forms (psychological, physical and sexual) during pregnancy (49.5%), stress (82%), and depression (33%) have an association that reflects the importance of acknowledging both of them as having a significant implication for the health of pregnant women in India. Analysis suggest that women who experienced DV during pregnancy are 4.9 times and 5.3 times more likely to suffer from stress and depressive symptoms than non-victims of DV respectively. The strong association reinforces the need to conduct routine screening during pregnancy to identify and respond to women with DV and S&D.

Effect of Aloe vera as a local drug delivery agent in the management of periodontal diseases: A systematic review and meta-analysis.

BACKGROUND: Aim of the present meta-analysis was to evaluate the effect of Aloe vera in various forms such as gel, mouthwash, and dentifrice on gingival and plaque index (PI) in comparison to various allopathic products such as chlorhexidine, metformin, chlorine dioxide, fluoridated toothpaste, and alendronate. MATERIALS AND METHODS: A comprehensive electronic search was conducted on PubMed/MEDLINE, GOOGLE SCHOLAR, and HAND SEARCH of reference list of archived articles published till January 2020. Randomized controlled trials were searched comparing the Aloe vera product with other products which used PI and gingival index (GI) to evaluate the outcomes. Finally, nine studies assessing PI and four studies evaluating GI were considered for the meta-analysis. After extracting the information, a risk of bias was estimated. The standardized mean differences (SMDs) and fixed and random effect models were obtained from the mean treatment differences. RESULTS: The estimates of SMD of PI from fixed effects (SMD = 0.271, 95% confidence interval [CI] = 0.00134-0.407, P < 0.001) and random effects (SMD = 0.288, 95% CI = 0.048-0.529, P = 0.019) were found slightly different, the models showed consistent results yielding positive and significant treatment effects. For GI fixed effects (SMD = 0.27, 95% CI = -0.035-0.575, P = 0.0803, not significant) and random effects (SMD = 0.259, 95% CI = 0.049-0.469, P = 0.016, significant) were found slightly different and positive. However, one model showed significant and another model showed nonsignificant treatment effects. CONCLUSION: Results from our meta-analyses confirmed the beneficial effects of A. vera in improving the periodontal parameters and hence may be considered as a safe alternative drug delivery agent for the management of periodontal diseases in future.

Topoisomerase II as a target for repurposed antibiotics in Candida albicans: an in silico study.

Fluoroquinolines, the widely used antibacterial antibiotics, have been shown to interact with human DNA topoisomerases supporting their use as repurposed cancer drugs in humans. In this communication molecular docking of eleven Fluoroquinolines against predicted structure of Candida albicans DNA Topoisomerase II is reported for the first time. C. albicans topoisomerase II structure prediction was done by using homology modeling tool. Ligand preparation and molecular docking with C. albicans topoisomerase II were done by using Autodock tool. These antibiotics formed hydrogen bond with good binding affinity at ARG 841, GLN803, ALA840 amino acid residues in the active site of C. albicans Topoisomerase II. We hypothesize that DNA toposiomerases may be the targets of Fluroquinoline group of antibiotics in C. albicans causing inhibition of growth.

Andrographis paniculata (Burm. F) Wall ex Nees: Antiviral properties.

Andrographis paniculata is home to a rich variety of molecules especially andrographolide and its derivatives. Clinical properties of the andrographolide are multifarious and include: analgesic, antipyretic, antiretroviral, antiproliferative, antimalarial, antithrombotic, antihyperglycemic, antiurolethial, antilesihmaniasis, hepatoprotective, immune-modulatory, protective against alcohol induced toxicity and cardioproetcive activity and anticancer activity. Andrographolide, neoandrographolide, dehydroandrographolide and several natural and synthetic derivatives of it: 14-deoxy-11,12-didehydroandrographolide and 14-deoxyandrographolide, dehydroandrographolide succinic acid monoester (DAMS), 14-ά-lipoyl andrographolide (AL-1), 14-acetyl-3,9-isopropyl-ideneandrographolide, 14-acetylandrographolide, 3,14,19-triacetylandrographolide, and 3,9-isopropyl-idene andrographolide, are shown to possess significant antiviral activity against HIV, influenza A, HBV, HCV, HPP and HSV. Studies on SARS CoV 2 is restricted to in silico molecular docking studies on viral targets and selected host target proteins. The main targets of andrographolide and its derivatives are fusion and adsorption of virus to the host cell, binding to viral receptor and co-receptor, enzymes involved in DNA/RNA/Genome replication by the virus, translation, post-translation and reverse transcription. Andrographolide as a drug is yet to reach its full therapeutic potential since this molecule shows low bioavailability. Andrographolide therapy is in need of an appropriate delivery system that may increase its bioavailability. Further high-quality studies are needed to firmly establish the clinical efficacy of the plant.

Imparting Multifunctionality by Utilizing Biporosity in a Zirconium-Based Metal-Organic Framework.

In this work, we have synthesized nanocomposites made up of a metal-organic framework (MOF) and conducting polymers by polymerization of specialty monomers such as pyrrole (Py) and 3,4-ethylenedioxythiophene (EDOT) in the voids of a stable and biporous Zr-based MOF (UiO-66). FTIR and Raman data confirmed the presence of polypyrrole (PPy) and poly3,4-ethylenedioxythiophene (PEDOT) in UiO-66-PPy and UiO-66-PEDOT nanocomposites, respectively, and PXRD data revealed successful retention of the structure of the MOF. HRTEM images showed successful incorporation of polymer fibers inside the voids of the framework. Owing to the intrinsic biporosity of UiO-66, polymer chains were observed to selectively occupy only one of the voids. This resulted in a remarkable enhancement (million-fold) of the electrical conductivity while the nanocomposites retain 60-70 % of the porosity of the original MOF. These semiconducting yet significantly porous MOF nanocomposite systems exhibited ultralow thermal conductivity. Enhanced electrical conductivity with lowered thermal conductivity could qualify such MOF nanocomposites for thermoelectric applications.

Molecular targets of biofabricated silver nanoparticles in Candida albicans.

We have analyzed the expressions of genes which regulate Ras-cAMP-EFG1 and CEK1-MAPK pathways involved in yeast to hyphal form morphogenesis in Candida albicans. The expression profile of genes associated with serum-induced morphogenesis showed reduced expressions of genes involved in these pathways by the treatment with biofabricated silver nanoparticles. Cell elongation gene, ECE1, was downregulated by 5.1 fold by the treatment of silver nanoparticles. Expression of hyphal inducer gene, TEC1 was downregulated by 6.28 fold. Negative regulators of yeast to hyphal transition, TUP1 and RFG1 were downregulated by 2.45 and 5.43 fold, respectively. Current study suggests that silver nanoparticles affect gene expression and may subsequently reduce virulence in C. albicans. Targeting genes involved in virulence may be an acceptable novel treatment strategy for pathogenic fungal infections.

The human muscarinic acetylcholine receptor antagonist, Dicyclomine targets signal transduction genes and inhibits the virulence factors in the human pathogen, Candida albicans.

Dicyclomine is a human muscarinic acetylcholine receptor antagonist used for the treatment of abdominal cramps. We are reporting here that dicyclomine can inhibit the in vitro growth and virulence factors of the human pathogen Candida albicans very effectively. Dicyclomine inhibited adhesion, early biofilm, mature biofilm, and planktonic growth. Yeast to hyphal form transition of C. albicans in various inducer media such as serum, proline, glucose, and N-acetylglucosamine was inhibited. Dicyclomine also could kill C. albicans cells within 15 min of exposure. Dicyclomine appears to inhibit the yeast to hyphal conversion by affecting signal transduction pathway. The expression of selected genes associated with yeast to hyphal form transition in serum in presence of dicyclomine was studied using real-time polymerase chain reaction (RtPCR). The RtPCR analysis showed that dicyclomine targets both cAMP pathway as well as MAPK cascade. Eight genes were upregulated. Out of these, three major upregulated genes were Bcy1, Tup1, and Mig1. Dicyclomine downregulated Ume6, Ece1, and Pde2 genes which are involved in cAMP signaling pathway and also downregulated the DNA binding protein gene, Rfg1. Dicyclomine significantly upregulated the master negative regulator of hyphal formation, Tup1. Based on this study we suggest that the muscarinic acetylcholine receptor antagonist, dicyclomine could be repositioned as a potential anti-Candida albicans as well as anti-virulence agent.

The Dietary Food Components Capric Acid and Caprylic Acid Inhibit Virulence Factors in Candida albicans Through Multitargeting.

Capric acid and caprylic acid are the dietary food components. They are found to inhibit the virulence factors like morphogenesis, adhesion, and biofilm formation in the human pathogenic yeast Candida albicans. Our study demonstrated that yeast-to-hyphal signal transduction pathways were affected by capric acid and caprylic acid. The expression profile of genes associated with serum-induced morphogenesis showed reduced expressions of Cdc35, Hwp1, Hst7, and Cph1 by the treatment with both the fatty acids. Cell elongation gene, Ece1, was surprisingly downregulated by 5208-fold by the treatment of caprylic acid. Nrg1 and Tup1, negative regulators of hyphal formation, were overexpressed in presence of capric or caprylic acid. Cell cycle studies revealed that capric and caprylic acids arrested cell cycle at G2/M and S phase. Targeting the virulence factors like yeast-to-hyphal transition is efficacious for treatment of opportunistic fungal infections. This research suggests that both capric and caprylic acid may be effective interventions for treating C. albicans yeast infections.

The antibacterial agent, moxifloxacin inhibits virulence factors of Candida albicans through multitargeting.

Fluoroquinolines are broad spectrum fourth generation antibiotics. Some of the Fluoroquinolines exhibit antifungal activity. We are reporting the potential mechanism of action of a fluoroquinoline antibiotic, moxifloxacin on the growth, morphogenesis and biofilm formation of the human pathogen Candida albicans. Moxifloxacin was found to be Candidacidal in nature. Moxifloxacin seems to inhibit the yeast to Hyphal morphogenesis by affecting signaling pathways. It arrested the cell cycle of C. albicans at S phase. Docking of moxifloxacin with predicted structure of C. albicans DNA Topoisomerase II suggests that moxifloxacin may bind and inhibit the activity of DNA Topoisomerase II in C. albicans. Moxifloxacin could be used as a dual purpose antibiotic for treating mixed infections caused by bacteria as well as C. albicans. In addition chances of developing moxifloxacin resistance in C. albicans are less considering the fact that moxifloxacin may target multiple steps in yeast to hyphal transition in C. albicans.