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Microbial Cell Factories Jan 2020Using an established CRISPR-Cas mediated genome editing technique for streptomycetes, we explored the combinatorial biosynthesis potential of the auroramycin...
Using an established CRISPR-Cas mediated genome editing technique for streptomycetes, we explored the combinatorial biosynthesis potential of the auroramycin biosynthetic gene cluster in Streptomyces roseosporous. Auroramycin is a potent anti-MRSA polyene macrolactam. In addition, auroramycin has antifungal activities, which is unique among structurally similar polyene macrolactams, such as incednine and silvalactam. In this work, we employed different engineering strategies to target glycosylation and acylation biosynthetic machineries within its recently elucidated biosynthetic pathway. Auroramycin analogs with variations in C-, N- methylation, hydroxylation and extender units incorporation were produced and characterized. By comparing the bioactivity profiles of five of these analogs, we determined that unique disaccharide motif of auroramycin is essential for its antimicrobial bioactivity. We further demonstrated that C-methylation of the 3, 5-epi-lemonose unit, which is unique among structurally similar polyene macrolactams, is key to its antifungal activity.
Topics: Anti-Bacterial Agents; Antifungal Agents; Biosynthetic Pathways; CRISPR-Cas Systems; Gene Editing; Metabolic Engineering; Methicillin-Resistant Staphylococcus aureus; Microbial Sensitivity Tests; Polyenes; Streptomyces
PubMed: 31906943
DOI: 10.1186/s12934-019-1274-y -
Journal of Global Antimicrobial... Jun 2022In this study, we examined the toxicities, including poisoning and overdoses, with polyene, azole, flucytosine and echinocandin antifungals reported to the Swiss... (Observational Study)
Observational Study
OBJECTIVES
In this study, we examined the toxicities, including poisoning and overdoses, with polyene, azole, flucytosine and echinocandin antifungals reported to the Swiss National Poison Centre.
METHODS
An observational cross-sectional study on antifungals was performed based on reports between 1995 and 2016 to Tox Info Suisse. Patient demographic and clinical characteristics were summarised among all reported calls, stratified by age group. In secondary analyses, we evaluated cases with clinical follow-up information.
RESULTS
In total, 149 cases were reported to the National Poison Centre during the study period, of which 49 (32.9%) were male and 91 (61.1%) were female, and 95 (63.8%) were adults and 54 (36.2%) were children (age ≤16 years). The most frequently reported drug class was azoles (136; 91.3%). In 31 cases (20.8%) reported by treating physicians, further clinical follow-up information was available. Nearly one-half of these patients were asymptomatic (15/31; 48.4%). In 11 patients (35.5%) among those with symptoms, the symptoms of toxicity were categorised with a strong causality to the respective antifungal. Clinical findings caused by triazoles were effects in the gastrointestinal tract, hallucinations and predelirium state. Clinical findings caused by polyenes were mostly minor symptoms with infusion-related effects or hypokalaemia. The severity was categorised as minor in 6 (54.5%) of 11 cases and as moderate in 5 cases (45.5%).
CONCLUSION
Despite high administered doses, no severe or fatal cases occurred within the study period. Although various toxicities can occur with antifungal administration and overdoses, they showed a favourable safety profile.
Topics: Adolescent; Adult; Antifungal Agents; Azoles; Child; Cross-Sectional Studies; Echinocandins; Female; Humans; Male; Polyenes
PubMed: 34896339
DOI: 10.1016/j.jgar.2021.11.010 -
Biochimica Et Biophysica Acta Feb 2016The influence of flavonoids and polyene antibiotics on the permeability of membranes has been investigated through measurements of calcein leakage from large unilamellar...
The influence of flavonoids and polyene antibiotics on the permeability of membranes has been investigated through measurements of calcein leakage from large unilamellar vesicles composed of DOPC:cholesterol (67:33 mol%). Phloretin and biochanin A have been shown to induce calcein release from liposomes, but quercetin, daidzein, and catechin have not. Differential scanning calorimetry has indicated a decreasing of melting temperature of DPPC vesicles by 1.5-2°C in the presence of phloretin and biochanin A. Quercetin, catechin, and daidzein have had almost no effect on the main transition temperature. Phloretin, biochanin A, and quercetin have significantly broadened the main transition peak of DPPC. Phloretin have increased a leakage induced by polyene antibiotics, whereas catechin and daidzein have not. Quercetin has slightly affected it. The effects of tested flavonoids on the polyene-induced calcein leakage and channel forming activity have been similar. The obtained data agree with the previously supposed hypothesis regarding the enhancement of polyene activity by reducing elastic stress near the lipid mouth of the nystatin pore. The inhibition of polyene channel forming activity by biochanin A observed in planar DOPC:cholesterol bilayers may be related to the flavonoid competition with cholesterol in the polyene-sterol channel complexes.
Topics: Catechin; Cholesterol; Genistein; Membranes, Artificial; Phloretin; Phosphatidylcholines; Polyenes; Quercetin
PubMed: 26657529
DOI: 10.1016/j.bbamem.2015.12.004 -
BMC Cancer Apr 2021Triazole, polyene, and echinocandin antifungal agents are extensively used to treat invasive fungal infections (IFIs); however, the optimal prophylaxis option is not... (Meta-Analysis)
Meta-Analysis
BACKGROUND AND AIM
Triazole, polyene, and echinocandin antifungal agents are extensively used to treat invasive fungal infections (IFIs); however, the optimal prophylaxis option is not clear. This study aimed to determine the optimal agent against IFIs for patients with hematological malignancies.
METHODS
Randomized controlled trials (RCTs) comparing the effectiveness of triazole, polyene, and echinocandin antifungal agents with each other or placebo for IFIs in patients with hematological malignancies were searched. This Bayesian network meta-analysis was performed for all agents.
RESULTS
The network meta-analyses showed that all triazoles, amphotericin B, and caspofungin, but not micafungin, reduced IFIs. Posaconazole was superior to fluconazole [odds ratio (OR), 0.30; 95% credible interval (CrI), 0.12-0.60], itraconazole (OR, 0.40; 95% CrI, 0.15-0.85), and amphotericin B (OR, 4.97; 95% CrI, 1.73-11.35). It also reduced all-cause mortality compared with fluconazole (OR, 0.35; 95% CrI, 0.08-0.96) and itraconazole (OR, 0.33; 95% CrI, 0.07-0.94), and reduced the risk of adverse events compared with fluconazole (OR, 0.02; 95% CrI, 0.00-0.03), itraconazole (OR, 0.01; 95% CrI, 0.00-0.02), posaconazole (OR, 0.02; 95% CrI, 0.00-0.03), voriconazole (OR, 0.005; 95% CrI, 0.00 to 0.01), amphotericin B (OR, 0.004; 95% CrI, 0.00-0.01), and caspofungin (OR, 0.05; 95% CrI, 0.00-0.42) despite no significant difference in the need for empirical treatment and the proportion of successful treatment.
CONCLUSIONS
Posaconazole might be an optimal prophylaxis agent because it reduced IFIs, all-cause mortality, and adverse events, despite no difference in the need for empirical treatment and the proportion of successful treatment.
Topics: Antifungal Agents; Echinocandins; Hematologic Neoplasms; Humans; Invasive Fungal Infections; Network Meta-Analysis; Polyenes; Pre-Exposure Prophylaxis; Publication Bias; Treatment Outcome; Triazoles
PubMed: 33853560
DOI: 10.1186/s12885-021-07973-8 -
Biochimica Et Biophysica Acta May 2005Carotenoids are an excellent example of where poor understanding of food structure, complexity of behaviour during digestion, and inter-individual differences in... (Review)
Review
Carotenoids are an excellent example of where poor understanding of food structure, complexity of behaviour during digestion, and inter-individual differences in response, lead to misinterpretation of study results. Four challenges associated with understanding and measuring carotenoid bioavailability are discussed: release of carotenoids from food structure and processing into an absorbable form (bioaccessibility), passage of carotenoids from gut lumen into the body (absorption), interpreting plasma response and inter-individual variation. Bioaccessibility of carotenoids is governed by characteristics of the food matrix, which affect the efficiency of physical, enzymic and chemical digestion. Carotenoids used as colorants are likely to be better absorbed because of the form in which they are dispersed in food. Extent of absorption of carotenoid supplements will depend on the proximity of dosing to the consumption of a fat-containing meal. Release of carotenoids from food plants occurs only when the plant cell is fractured and this occurs only during food preparation, processing and/or mastication, not during digestion. Following release from the food matrix, the major limiting factor is solubility of carotenoids in digesta. Absorption studies are best carried out by measuring chylomicron carotenoid excursion, with modelling of chylomicron turnover rate. In this way, inter-individual differences in lipoprotein metabolism can, in part, be taken into account before formulating conclusions on the rate and extent of absorption.
Topics: Animals; Biological Availability; Carotenoids; Chylomicrons; Diet; Food Additives; Humans; Intestinal Absorption; Lipid Metabolism; Lipids; Polyenes; Solubility
PubMed: 15949674
DOI: 10.1016/j.bbadis.2004.11.012 -
Biology of Blood and Marrow... Feb 2004Invasive fungal infections pose major management problems for clinicians caring for hematopoietic cell transplant patients. Two major fungal genera, Candida and... (Review)
Review
Invasive fungal infections pose major management problems for clinicians caring for hematopoietic cell transplant patients. Two major fungal genera, Candida and Aspergillus, account for most fungal infections. Rates of systemic Candida infection range from 15% to 25%, mostly in the pre-engraftment period. Prophylaxis by fluconazole has dramatically reduced the frequency of early Candida infections. Caspofungin has recently been shown to offer an excellent alternative to amphotericin B (with less toxicity) or fluconazole (with a broader spectrum) for therapy of systemic Candida infections. Aspergillus infections occur in 15% to 20% of allogeneic hematopoietic cell transplant patients, most frequently in the post-engraftment period; they are associated with a severe diminution of cell-mediated immune responses by graft-versus-host disease and prolonged corticosteroid use. Voriconazole, a recently introduced broad-spectrum azole, has excellent activity against Aspergillus and is generally well tolerated. Voriconazole currently offers the best prospect for success and tolerance as a first-line treatment for aspergillosis. Second-line therapies include lipid formulations of amphotericin B, caspofungin, or intravenous itraconazole. Unfortunately, early initiation of therapy for aspergillosis is frequently not possible because of inaccurate diagnostics. One new diagnostic, the galactomannan assay, has recently been approved, and others are in development; these offer promise for earlier diagnosis without the need for invasive procedures. It is hoped that these new therapies and new diagnostics will usher in a new era of antifungal therapy.
Topics: Antifungal Agents; Azoles; Echinocandins; Fungal Proteins; Hematopoietic Stem Cell Transplantation; Humans; Mycoses; Nucleosides; Peptides; Peptides, Cyclic; Polyenes
PubMed: 14750074
DOI: 10.1016/j.bbmt.2003.09.014 -
Organic Letters Mar 2021Although substituted benzimidazoles are common substructures in bioactive small molecules, synthetic methods for their derivatization are still limited. Previously,...
Although substituted benzimidazoles are common substructures in bioactive small molecules, synthetic methods for their derivatization are still limited. Previously, several enantioselective allylation reactions of benzimidazoles were reported that functionalize the nucleophilic nitrogen atom. Herein we describe a reversal of this inherent selectivity toward -allylation by using electrophilic -OPiv benzimidazoles with readily available 1,3-dienes as nucleophile precursors. This CuH-catalyzed approach utilizes mild reaction conditions, exhibits broad functional-group compatibility, and exclusively forms the C2-allylated product with excellent stereoselectivity.
Topics: Allyl Compounds; Benzimidazoles; Catalysis; Copper; Molecular Structure; Polyenes; Stereoisomerism
PubMed: 33646778
DOI: 10.1021/acs.orglett.1c00306 -
Clinical Microbiology and Infection :... Jan 2003The vast number and variety of chemotherapeutic agents isolated from microbial natural products and used to treat bacterial infections have greatly contributed to the... (Review)
Review
The vast number and variety of chemotherapeutic agents isolated from microbial natural products and used to treat bacterial infections have greatly contributed to the improvement of human health during the past century. However, only a limited number of antifungal agents (polyenes and azoles, plus the recently introduced caspofungin acetate) are currently available for the treatment of life-threatening fungal infections. Furthermore, the prevalence of systemic fungal infections has increased significantly during the past decade. For this reason, the development of new antifungal agents, preferably with novel mechanisms of action, is an urgent medical need. A selection of antifungal agents in early stages of development, produced by micro-organisms, is summarized in this review. The compounds are classified according to their mechanisms of action, covering inhibitors of the synthesis of cell wall components (glucan, chitin and mannoproteins), of sphingolipid synthesis (serine palmitoyltransferase, ceramide synthase, inositol phosphoceramide synthase and fatty acid elongation) and of protein synthesis (sordarins). In addition, some considerations related to the chemotaxonomy of the producing organisms and some issues relevant to antifungal drug discovery are also discussed.
Topics: Animals; Anti-Bacterial Agents; Antifungal Agents; Azoles; Biological Products; Caspofungin; Chitin; Echinocandins; Glucans; Humans; Lipopeptides; Membrane Glycoproteins; Mycoses; Peptides; Peptides, Cyclic; Polyenes; Protein Synthesis Inhibitors; Sphingolipids
PubMed: 12691539
DOI: 10.1046/j.1469-0691.2003.00489.x -
Journal of Infection and Chemotherapy :... Oct 2019Candida auris is a multidrug-resistant and emergent pathogen that has caused healthcare-associated infection outbreaks. Recently, C. auris has spread worldwide;... (Review)
Review
Candida auris is a multidrug-resistant and emergent pathogen that has caused healthcare-associated infection outbreaks. Recently, C. auris has spread worldwide; nevertheless, it was unexpectedly rare before 2009. Based on the molecular epidemiological analysis, C. auris may independently emerge at specific areas at first and recently may be transmitted to other continents. As C. auris cannot be detected using conventional methods, internally transcribed spacers, D1/D2 regions of the 26S rDNA sequencing, and/or matrix-assisted laser desorption ionization time-of-flight mass spectrometry method can be selected as comparatively accessible choices. Thus, detection of C. auris using the conventional method might be underestimated. In Japan, all C. auris strains were isolated from ear specimen and not from invasive mycoses. Japan strains were classified as an East Asian clade under a single clone. Although colonization, virulence, and infection pattern are almost the same as with other Candida species, its antifungal resistance is different. Fluconazole resistance is notably common, but resistance to all three classes of antifungals (azole, polyene, and echinocandin) rarely exists. Once C. auris is detected, screening, emphasis on hand hygiene adherence, use of single-patient room isolation, contact precaution, surveillance, and eradication from the environment and patients are appropriately required for infection control.
Topics: Antifungal Agents; Azoles; Candida; Candidiasis; Drug Resistance, Multiple, Fungal; Echinocandins; Fluconazole; Humans; Japan; Microbial Sensitivity Tests; Polyenes; Prevalence
PubMed: 31257156
DOI: 10.1016/j.jiac.2019.05.034 -
Marine Drugs Oct 2022Naturally occurring epimeric hydroxy-polyene glycerol ether pericharaxins A () and B () were isolated from the calcarean sponge . The structural and stereochemical...
Naturally occurring epimeric hydroxy-polyene glycerol ether pericharaxins A () and B () were isolated from the calcarean sponge . The structural and stereochemical characterization of both diastereoisomers were established on the basis of spectroscopic data analysis and total synthesis in seven steps. The mixture of pericharaxins A () and B () was proven to be epimeric by chiral-phase HPLC analysis of both synthetic and natural samples. Further separation of the epimers and application of Mosher's method to the synthetic compounds allowed unequivocal absolute configuration assignment. While natural products and the synthetic intermediates were shown to be non-cytotoxic on the HCT116 cell line, the endochondral differentiation activity using human type X collagen transcription activity in ATDC5 cells is interesting.
Topics: Animals; Humans; Glyceryl Ethers; Collagen Type X; Polyenes; Porifera; Biological Products; Molecular Structure; Stereoisomerism
PubMed: 36286459
DOI: 10.3390/md20100635