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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 -
Organic Letters Jun 2022We describe a Xantphos-containing dinuclear palladium complex-enabled geminal aminoallylation of diazocarbonyl compounds, which selectively provides a range of...
We describe a Xantphos-containing dinuclear palladium complex-enabled geminal aminoallylation of diazocarbonyl compounds, which selectively provides a range of quaternary α-amino esters. Direct N-H insertion, allylic alkylation of amino nucleophiles, and diene formation were not observed under standard conditions. Mechanistic studies indicated that a relayed pathway via allylation of the N-H insertion product or [2,3]-sigmatropic rearrangement of an ylide intermediate was unlikely.
Topics: Alkylation; Allyl Compounds; Azo Compounds; Catalysis; Palladium; Polyenes
PubMed: 35657704
DOI: 10.1021/acs.orglett.2c01399 -
Organic Letters Jun 2022A copper-catalyzed regioselective Markovnikov 3,4-hydrosilylation of 2-substituted 1,3-dienes has been accomplished. A wide range of 2-substituted 1,3-dienes and...
A copper-catalyzed regioselective Markovnikov 3,4-hydrosilylation of 2-substituted 1,3-dienes has been accomplished. A wide range of 2-substituted 1,3-dienes and trihydrosilanes are compatible under the optimal conditions. The bisphosphine ligand with a rigid backbone provides the Markovnikov 3,4-hydrosilylation product in better yield and selectivity. Besides, the synthetic utilities of the allylsilanes also were demonstrated by their flexible derivatizations.
Topics: Catalysis; Copper; Polyenes
PubMed: 35648807
DOI: 10.1021/acs.orglett.2c01558 -
Organic & Biomolecular Chemistry Jun 2022Alternapyrone is a highly methylated polyene α-pyrone biosynthesised by a highly reducing polyketide synthase. Mutations of the catalytic dyad residues, H1578A/Q and...
Alternapyrone is a highly methylated polyene α-pyrone biosynthesised by a highly reducing polyketide synthase. Mutations of the catalytic dyad residues, H1578A/Q and E1604A, of the -methyltransferase domain resulted in either significantly reduced or no production of alternapyrone, indicating the importance of -methylation for alternapyrone biosynthesis.
Topics: Methylation; Polyenes; Polyketide Synthases; Triterpenes
PubMed: 35695066
DOI: 10.1039/d2ob00947a -
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 -
Nature Communications Jul 2021Aurantinins (ARTs) are antibacterial polyketides featuring a unique 6/7/8/5-fused tetracyclic ring system and a triene side chain with a carboxyl terminus. Here we...
Aurantinins (ARTs) are antibacterial polyketides featuring a unique 6/7/8/5-fused tetracyclic ring system and a triene side chain with a carboxyl terminus. Here we identify the art gene cluster and dissect ART's C-methyl incorporation patterns to study its biosynthesis. During this process, an apparently redundant methyltransferase Art28 was characterized as a malonyl-acyl carrier protein O-methyltransferase, which represents an unusual on-line methyl esterification initiation strategy for polyketide biosynthesis. The methyl ester bond introduced by Art28 is kept until the last step of ART biosynthesis, in which it is hydrolyzed by Art9 to convert inactive ART 9B to active ART B. The cryptic reactions catalyzed by Art28 and Art9 represent a protecting group biosynthetic logic to render the ART carboxyl terminus inert to unwanted side reactions and to protect producing organisms from toxic ART intermediates. Further analyses revealed a wide distribution of this initiation strategy for polyketide biosynthesis in various bacteria.
Topics: Acyl Carrier Protein; Anti-Bacterial Agents; Bacillus subtilis; Bacterial Proteins; Biosynthetic Pathways; Esterification; Gram-Negative Bacteria; Gram-Positive Bacteria; Methyltransferases; Microbial Sensitivity Tests; Models, Chemical; Molecular Structure; Multigene Family; Polyenes; Polyketides
PubMed: 34301953
DOI: 10.1038/s41467-021-24846-7 -
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 -
Angewandte Chemie (International Ed. in... May 2022Epoxy and aziridinyl enolsilanes react as oxyallylic cation equivalents in highly chemo- and diastereoselective intramolecular (3+2) cycloadditions with a range of...
Epoxy and aziridinyl enolsilanes react as oxyallylic cation equivalents in highly chemo- and diastereoselective intramolecular (3+2) cycloadditions with a range of dienes and olefins. With acyclic dienes, the (3+2) cycloaddition outcompetes the (4+3) pathway traditionally observed in this kind of system almost exclusively. With both conjugated dienes and isolated olefins, excellent diastereoselectivities are observed, and cycloadducts can be obtained in optically-enriched forms. Computational studies indicate that the stepwise (3+2) cycloaddition involves an activated epoxy/aziridinyl intermediate and the conformational flexibility of the intermediate determines the preference for (3+2) cycloadduct formation. Further transformations of the (3+2) cycloadducts produce densely functionalized trans-hydrindane scaffolds.
Topics: Alkenes; Cycloaddition Reaction; Molecular Conformation; Polyenes; Stereoisomerism
PubMed: 35274431
DOI: 10.1002/anie.202116099 -
Organic & Biomolecular Chemistry Dec 2022Conjugated dienes have occupied a pivotal position in the field of synthetic organic chemistry and medicinal chemistry. They act as important synthons for the synthesis... (Review)
Review
Conjugated dienes have occupied a pivotal position in the field of synthetic organic chemistry and medicinal chemistry. They act as important synthons for the synthesis of various biologically important molecules and therefore, gain tremendous attention worldwide. A wide range of synthetic routes to access these versatile molecules have been developed in the past decades. Transition metal-catalyzed cross-dehydrogenative coupling (CDC) has emerged as one of the utmost front-line research areas in current synthetic organic chemistry due to its high atom economy, efficiency, and viability. In this review, an up-to-date summary including scope, limitations, mechanistic studies, stereoselectivities, and synthetic applications of transition metal-catalyzed double C-H bond activation for the synthesis of conjugated dienes has been reported since 2013. The literature reports mentioned in this review have been classified into three different categories, (a) C-C bond formation oxidative homo-coupling of terminal alkenes; (b) C-C bond formation non-directed oxidative cross-coupling of linear/cyclic alkenes and terminal/internal alkenes, and (c) C-C bond formation oxidative cross-coupling of directing group bearing alkenes and terminal/internal alkenes. Overall, this review aims to provide a concise overview of the current status of the considerable development in this field and is expected to stimulate further innovation and research in the future.
Topics: Catalysis; Alkenes; Polyenes; Transition Elements; Oxidation-Reduction
PubMed: 36412483
DOI: 10.1039/d2ob01646j