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Journal of Industrial Microbiology &... Nov 2016A polyene compound NPP identified in Pseudonocardia autotrophica was shown to contain an aglycone identical to nystatin, but to harbor a unique disaccharide moiety that...
A polyene compound NPP identified in Pseudonocardia autotrophica was shown to contain an aglycone identical to nystatin, but to harbor a unique disaccharide moiety that led to higher solubility and reduced hemolytic activity. Recently, it was revealed that the final step of NPP (nystatin-like polyene) biosynthesis is C10 regio-specific hydroxylation by the cytochrome P450 hydroxylase (CYP) NppL (Kim et al. [7]). Through mutation and cross-complementation, here we found that NppL preferred a polyene substrate containing a disaccharide moiety for C10 hydroxylation, while its orthologue NysL involved in nystatin biosynthesis showed no substrate preference toward mono- and disaccharide moieties, suggesting that two homologous polyene CYPs, NppL and NysL might possess a unique domain recognizing a sugar moiety. Two hybrid NppL constructs containing the C-terminal domain of NysL exhibited no substrate preference toward 10-deoxy NPP and 10-deoxy nystatin-like NysL, implying that the C-terminal domain plays a major role in differentiating the sugar moiety responsible for substrate specificity. Further C-terminal domain dissection of NppL revealed that the last fifty amino acids play a critical role in determining substrate specificity of polyene-specific hydroxylation, setting the stage for the biotechnological application of hydroxyl diversification for novel polyene biosynthesis in actinomycetes.
Topics: Actinomycetales; Bacterial Proteins; Cytochrome P-450 Enzyme System; Disaccharides; Hydroxylation; Nystatin; Polyenes; Protein Domains; Substrate Specificity
PubMed: 27581440
DOI: 10.1007/s10295-016-1813-z -
Applied and Environmental Microbiology Apr 2021A group of polyene macrolides mainly composed of two constituents was isolated from the fermentation broth of Men-myco-93-63, which was isolated from soil where potato...
A group of polyene macrolides mainly composed of two constituents was isolated from the fermentation broth of Men-myco-93-63, which was isolated from soil where potato scabs were repressed naturally. One of these macrolides was roflamycoin, which was first reported in 1968, and the other was a novel compound named Men-myco-A, which had one methylene unit more than roflamycoin. Together, they were designated RM. This group of antibiotics exhibited broad-spectrum antifungal activities against 17 plant-pathogenic fungi, with 50% effective concentrations (EC) of 2.05 to 7.09 μg/ml and 90% effective concentrations (EC) of 4.32 to 54.45 μg/ml, which indicates their potential use in plant disease control. Furthermore, their biosynthetic gene cluster was identified, and the associated biosynthetic assembly line was proposed based on a module and domain analysis of polyketide synthases (PKSs), supported by findings from gene inactivation experiments. Men-myco-93-63 is a biocontrol strain that has been studied in our laboratory for many years and exhibits a good inhibitory effect in many crop diseases. Therefore, the identification of antimicrobial metabolites is necessary and our main objective. In this work, chemical, bioinformatic, and molecular biological methods were combined to identify the structures and biosynthesis of the active metabolites. This work provides a new alternative agent for the biological control of plant diseases and is helpful for improving both the properties and yield of the antibiotics via genetic engineering.
Topics: Ascomycota; Bacterial Proteins; Biological Control Agents; Biosynthetic Pathways; Macrolides; Multigene Family; Mycelium; Plant Diseases; Polyenes; Streptomyces
PubMed: 33637575
DOI: 10.1128/AEM.03157-20 -
ACS Infectious Diseases Aug 2020Amphotericin B (AmB, ) is the drug of choice for treating the most serious systemic fungal or protozoan infections. Nevertheless, its application is limited by low...
Amphotericin B (AmB, ) is the drug of choice for treating the most serious systemic fungal or protozoan infections. Nevertheless, its application is limited by low solubility in aqueous media and serious side effects such as infusion-related reactions, hemolytic toxicity, and nephrotoxicity. Owing to these limitations, it is essential to search for the polyene derivatives with better chemotherapeutic properties. With the objective of obtaining AmB derivatives with lower self-aggregation and improved solubility, we synthesized a series of amides of AmB bearing an additional basic group in the introduced residue. The screening of antifungal activity in vitro revealed that -(2-aminoethyl)amide of AmB (amphamide, ) had superior antifungal activity compared to that of the paternal AmB. Preclinical studies in mice confirmed that compound had a much lower acute toxicity and higher antifungal efficacy in the model of mice candidosis sepsis compared with that of AmB (). Thus, the discovered amphamide is a promising drug candidate for the second generation of polyene antibiotics and is also prospective for in-depth preclinical and clinical evaluation.
Topics: Amphotericin B; Animals; Anti-Bacterial Agents; Antifungal Agents; Mice; Pharmaceutical Preparations; Polyenes; Prospective Studies
PubMed: 32598131
DOI: 10.1021/acsinfecdis.0c00068 -
Journal of the American Chemical Society Dec 2014The total synthesis of hongoquercin B was carried out in 9 steps from trans,trans-farnesyl acetate using a palladium catalyzed decarboxylative π-farnesyl rearrangement...
The total synthesis of hongoquercin B was carried out in 9 steps from trans,trans-farnesyl acetate using a palladium catalyzed decarboxylative π-farnesyl rearrangement of a diketo-dioxinone ester, aromatization and cationic diene-epoxide cyclization as key steps. This cascade tetracyclization simplifies the synthesis of terpenoid resorcylate natural products.
Topics: Cyclization; Molecular Conformation; Polyenes; Polyketides; Sesquiterpenes; Stereoisomerism
PubMed: 25423048
DOI: 10.1021/ja511534x -
Acta Pharmaceutica Nordica 1990The stereochemical complexity of roflamycoin and other polyene macrolide antibiotics presents a formidable challenge to the synthetic chemist, and the lack of obvious... (Review)
Review
The stereochemical complexity of roflamycoin and other polyene macrolide antibiotics presents a formidable challenge to the synthetic chemist, and the lack of obvious disconnections makes the retrosynthetic analysis very complex. The alternating (1, 3, 5, ...) polyol chain in roflamycoin is difficult to synthesize in part because there is no simple method to assemble these chains from smaller subunits. We have addressed this problem and developed a simple, convergent method for assembling alternating polyol chains. It is designed around a new class of 1,3-diol synthons: 6-alkyl-4-thiophenyl-1,3-dioxanes. These 1,3-diol synthons are readily available from either homoallylic alcohols or beta-hydroxyesters, which are themselves readily prepared in optically pure form. Reduction of these synthons under the appropriate conditions gives configurationally stable alkyllithiums with either syn or anti stereochemistry. Reaction with electrophiles produces protected syn or anti-1,3-diols.
Topics: Anti-Bacterial Agents; Macrolides; Polyenes; Stereoisomerism
PubMed: 2200427
DOI: No ID Found -
Chemistry & Biology May 2005Streptomyces diastaticus var. 108, a newly isolated strain, was recently characterized as a producer of two polyene macrolide antibiotics (rimocidin and CE-108), and the... (Comparative Study)
Comparative Study
Streptomyces diastaticus var. 108, a newly isolated strain, was recently characterized as a producer of two polyene macrolide antibiotics (rimocidin and CE-108), and the biosynthetic gene cluster was partially characterized. When the producer strain was genetically modified by transformation with some engineered SCP2*-derived vectors carrying the ermE gene, two previously uncharacterized macrolides were detected in the fermentation broth of the recombinant strain and chemically characterized as the amides of the parental polyene carboxylic acids. The biological activity and some in vitro toxicity assays showed that this chemical modification resulted in pharmaceuticals with improved biological properties compared with the parental products.
Topics: Antifungal Agents; Erythrocytes; Fungi; Genes, Bacterial; Hemolysis; Humans; Macrolides; Methyltransferases; Monosaccharides; Polyenes; Streptomyces
PubMed: 15911374
DOI: 10.1016/j.chembiol.2005.02.015 -
Angewandte Chemie (International Ed. in... Feb 2018While type II polyketide synthases (PKSs) are known for producing aromatic compounds, a phylogenetically new subfamily of type II PKSs have been recently proposed to...
While type II polyketide synthases (PKSs) are known for producing aromatic compounds, a phylogenetically new subfamily of type II PKSs have been recently proposed to synthesize polyene structures. Here we report in vitro analysis of such a type II PKS, IgaPKS for ishigamide biosynthesis. The ketoreductase (Iga13) and dehydratase (Iga16) were shown to catalyze the reduction of a β-keto group and dehydration of a β-hydroxy group, respectively, to form a trans double bond. Incubation of the acyl carrier protein (Iga10), the ketosynthase/chain length factor complex (Iga11-Iga12), Iga13 and Iga16 with malonyl and hexanoyl-CoAs and NADPH followed by KOH hydrolysis resulted in the formation of four unsaturated carboxylic acids (C , C , C , and C ), indicating that IgaPKS catalyzes tetraene formation by repeating the cycle of condensation, keto-reduction and dehydration with strict stereo-specificity. We propose "highly reducing type II PKS subfamily" for the polyene-producing type II PKSs.
Topics: Amides; Biocatalysis; Chromatography, High Pressure Liquid; Dehydration; Kinetics; Mass Spectrometry; Oxidation-Reduction; Polyenes; Polyketide Synthases; Stereoisomerism
PubMed: 29265713
DOI: 10.1002/anie.201709636 -
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 -
The Journal of Antibiotics Jan 2016
Topics: Macrolides; Molecular Structure; Polyenes; Streptomyces
PubMed: 26174177
DOI: 10.1038/ja.2015.76 -
Organic Letters Feb 2009A mutualist actinomycete of the southern pine beetle, Dendroctonus frontalis, produces a polyene peroxide with pronounced antifungal activity. Its structure, absolute...
A mutualist actinomycete of the southern pine beetle, Dendroctonus frontalis, produces a polyene peroxide with pronounced antifungal activity. Its structure, absolute configuration, and biological activity were determined by spectral analysis, chemical modification followed by the modified Mosher method, and growth inhibitory assays, respectively.
Topics: Acetates; Animals; Antifungal Agents; Coleoptera; Molecular Structure; Peroxides; Pinus; Polyenes; Streptomyces
PubMed: 19125624
DOI: 10.1021/ol802709x