SciCombinator

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Concept: Ergosterol

6

Vitamin D (D) supplements are indispensable for its world-wide deficiency. Controversy continues on ergocalciferol (D2) and cholecalciferol (D3) relative potency as well as on dosing-schedule and sex role in raising 25-hydroxy D (25(OH)D) level, the best indicator of D status.

Concepts: Pharmacology, Vitamin D, Epidemiology, Randomized controlled trial, Vitamins, Ergosterol, Ergocalciferol, Secosteroids

6

Efficient and pathogen-specific antifungal agents are required to mitigate drug resistance problems. Here we present cationic small molecules that exhibit excellent microbial selectivity with minimal host toxicity. Unlike typical cationic polymers possessing molecular weight distributions, these compounds have an absolute molecular weight aiding in isolation and characterization. However, their specific molecular recognition motif (terephthalamide-bisurea) facilitates spontaneous supramolecular self-assembly manifesting in several polymer-like properties. Computational modelling of the terephthalamide-bisurea structures predicts zig-zag or bent arrangements where distal benzyl urea groups stabilize the high-aspect ratio aqueous supramolecular assemblies. These nanostructures are confirmed by transmission electron microscopy and atomic force microscopy. Antifungal activity against drug-sensitive and drug-resistant strains with in vitro and in vivo biocompatibility is observed. Additionally, despite repeated sub-lethal exposures, drug resistance is not induced. Comparison with clinically used amphotericin B shows similar antifungal behaviour without any significant toxicity in a C. albicans biofilm-induced mouse keratitis model.

Concepts: Electron, Molecule, Chemistry, Atom, Nanotechnology, Supramolecular chemistry, Flucytosine, Ergosterol

6

Over the last 50 years or so, amphotericin has been widely employed in treating life-threatening systemic fungal infections. Its usefulness in the clinic, however, has always been circumscribed by its dose-limiting side-effects, and it is also now compromised by an increasing incidence of pathogen resistance. Combating these problems through development of new anti-fungal agents requires detailed knowledge of the drug’s molecular mechanism, but unfortunately this is far from clear. Neutron diffraction studies of the drug’s incorporation within lipid-sterol membranes have here been performed to shed light on this problem. The drug is shown to disturb the structures of both fungal and mammalian membranes, and co-localises with the membrane sterols in a manner consistent with trans-membrane pore formation. The differences seen in the membrane lipid ordering and in the distributions of the drug-ergosterol and drug-cholesterol complexes within the membranes are consistent with the drug’s selectivity for fungal vs. human cells.

Concepts: Immune system, Game theory, Bacteria, Cell membrane, Antifungals, Flucytosine, Order theory, Ergosterol

5

With the World Health Organization reporting over 30,000 deaths and 200-400,000 new cases annually, visceralLeishmaniasis is a serious disease affecting some of the world’s poorest people. As drug resistance continues to rise, there is a huge unmet need to improve treatment. Miltefosine remains one of the main treatments forLeishmaniasis, yet its mode of action (MoA) is still unknown. Understanding the MoA of this drug and parasite response to treatment could help pave the way for new, more successful treatments forLeishmaniasis. A novel method has been devised to study the metabolome and lipidome ofLeishmania donovaniaxenic amastigotes treated with miltefosine. Miltefosine caused a dramatic decrease in many membrane phospholipids (PLs), in addition to amino acid pools, while sphingolipids (SLs) and sterols increased.Leishmania majorpromastigotes devoid of SL biosynthesis through loss of the serine palmitoyl transferase gene (ΔLCB2) were 3-fold less sensitive to miltefosine than WT parasites. Changes in the metabolome and lipidome of miltefosine treatedL. majormirrored those ofL. donovaniA lack of SLs in the ΔLCB2 was matched by substantial alterations in sterol content. Together these data indicate that SLs and ergosterol are important for miltefosine sensitivity and perhaps, MoA.

Concepts: Cholesterol, Amino acid, Metabolism, Cell membrane, World Health Organization, Ergosterol, Sphingolipid, Sterol

4

Amphotericin B has emerged as the therapy of choice for use against the leishmaniases. Administration of the drug in its liposomal formulation as a single injection is being promoted in a campaign to bring the leishmaniases under control. Understanding the risks and mechanisms of resistance is therefore of great importance. Here we select amphotericin B-resistant Leishmania mexicana parasites with relative ease. Metabolomic analysis demonstrated that ergosterol, the sterol known to bind the drug, is prevalent in wild-type cells, but diminished in the resistant line, where alternative sterols become prevalent. This indicates that the resistance phenotype is related to loss of drug binding. Comparing sequences of the parasites' genomes revealed a plethora of single nucleotide polymorphisms that distinguish wild-type and resistant cells, but only one of these was found to be homozygous and associated with a gene encoding an enzyme in the sterol biosynthetic pathway, sterol 14α-demethylase (CYP51). The mutation, N176I, is found outside of the enzyme’s active site, consistent with the fact that the resistant line continues to produce the enzyme’s product. Expression of wild-type sterol 14α-demethylase in the resistant cells caused reversion to drug sensitivity and a restoration of ergosterol synthesis, showing that the mutation is indeed responsible for resistance. The amphotericin B resistant parasites become hypersensitive to pentamidine and also agents that induce oxidative stress. This work reveals the power of combining polyomics approaches, to discover the mechanism underlying drug resistance as well as offering novel insights into the selection of resistance to amphotericin B itself.

Concepts: DNA, Gene, Bacteria, Evolution, Metabolism, Adenosine triphosphate, Enzyme, Ergosterol

3

Vitamin D is a particularly important sterol hormone with evidence emerging of its beneficial effects well beyond bone. In consequence of this and increased global recognition of vitamin D deficiency in the general population, there has been a resurgence in treatment with vitamin D preparations. However, the increasing use of vitamin D treatments has also seen a substantial increase in the numbers of reports of vitamin D intoxication with the majority (75%) of reports published since 2010. Many of these cases are a consequence of inappropriate prescribing, the use of high dose over-the-counter preparations or unlicensed preparations. This review highlights that the majority of cases were preventable and discusses the inappropriate use of poorly formulated, and unlicensed vitamin D preparations.

Concepts: Bone, Vitamin D, Vitamin, Vitamins, Medical prescription, Ergosterol

3

The antifungal effects of the novel triazole, PC1244, designed for topical or inhaled administration, againstA. fumigatushave been tested in a range ofin vitroandin vivostudies. PC1244 demonstrated potent antifungal activities against clinicalA. fumigatusisolates (N=96) with a MIC range of 0.016–0.25 μg/ml, whereas the MIC range for voriconazole was 0.25–0.5 μg/ml. PC1244 was a strong tight-binding inhibitor of recombinantA. fumigatusCYP51A and CYP51B (sterol 14α-demethylase) enzymes and strongly inhibited ergosterol synthesis inA. fumigatuswith an IC50of 8 nM. PC1244 was effective against a broad spectrum of pathogenic fungi (MIC ranged from <0.0078∼2 μg/ml), especially onAspergillus terreus,Trichophyton rubrum,Candida albicans,Candida glabrata,Candida krusei,Cryptococcus gattii,Cryptococcus neoformans and Rhizopus oryzaePC1244 also proved to be quickly absorbed into bothA. fumigatushyphae and bronchial epithelial cells, producing persistent antifungal effects. In addition, PC1244 showed fungicidal activity (MFC, 2 μg/ml), which was 8-fold more potent than voriconazole.In vivo, once daily intranasal administration of PC1244 (3.2 ∼ 80μg/mL) to temporarily neutropenic, immunocompromised mice 24h after inoculation with itraconazole-susceptibleA. fumigatussubstantially reduced fungal load in the lung, galactomannan in serum and circulating inflammatory cytokines. Furthermore, 7 days extended prophylaxis with PC1244 showed superiorin vivoeffects when compared against 1 day of prophylactic treatment, suggesting accumulation of the effects of PC1244. Thus, PC1244 has the potential to be a novel therapy for the treatment ofA. fumigatusinfection in the lungs of humans.

Concepts: Lung, Fungus, Epithelium, Novel, Mycology, Ergosterol, Antifungal drug, Human lung

3

The antifungal activity of some statins against different fungal species has been reported. Thus, at the first moment, the in vitro antifungal activity of simvastatin, atorvastatin and pravastatin was tested against Candida spp. and Cryptococcus spp. Then, in a second approach, considering that the best results were obtained for simvastatin, this drug was evaluated in combination with antifungal drugs against planktonic growth and tested against biofilms of Candida spp. and Cryptococcus spp. Drug susceptibility testing was performed using the microdilution broth method, as described by the Clinical and Laboratory Standards Institute. The interaction between simvastatin and antifungals against planktonic cells was analyzed by calculating the fractional inhibitory concentration index. Regarding biofilm susceptibility, simvastatin was tested against growing biofilm and mature biofilm of one strain of each tested yeast species. Simvastatin showed inhibitory effect against Candida spp. and Cryptococcus spp. with minimum inhibitory concentration values ranging from 15.6 to 1000mgL(-1) and from 62.5 to 1000mgL(-1), respectively. The combination of simvastatin with itraconazole and fluconazole showed synergism against Candida spp. and Cryptococcus spp., while the combination of simvastatin with amphotericin B was synergistic only against Cryptococcus spp. Concerning the biofilm assays, simvastatin was able to inhibit both growing biofilm and mature biofilm of Candida spp. and Cryptococcus spp. The present study showed that simvastatin inhibits planktonic cells and biofilms of Candida and Cryptococcus species.

Concepts: Archaea, Fungus, Statin, Antifungals, Flucytosine, Candidiasis, Ergosterol, Antifungal drug

3

Itraconazole, a US Food and Drug Administration-approved antifungal drug, inhibits the Hedgehog (HH) signaling pathway, a crucial driver of basal cell carcinoma (BCC) tumorigenesis, and reduces BCC growth in mice. We assessed the effect of itraconazole on the HH pathway and on tumor size in human BCC tumors.

Concepts: Clinical trial, Cancer, Squamous cell carcinoma, Basal cell carcinoma, Antifungals, Ergosterol, Hedgehog signaling pathway, Fluconazole

2

Oral candidiasis (OC) is a common oral fungal infection. Recently, miconazole mucoadhesive tablets have been gaining attention for OC treatment. Despite trials in patients with human immunodeficiency virus and cancer, evidence of its application in the large-scale, general population with OC is lacking. This study aimed to evaluate the efficacy and safety of miconazole nitrate mucoadhesive tablets in comparison with itraconazole capsules for OC treatment.

Concepts: HIV, AIDS, Immune system, Virus, Randomized controlled trial, Candidiasis, Ergosterol, Janssen Pharmaceutica