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Postgraduate Medical Journal Sep 1979The mode of action of the polyene antibiotics is reviewed together with the effect of genetic and environmental factors on sensitive organisms. The future prospects of...
The mode of action of the polyene antibiotics is reviewed together with the effect of genetic and environmental factors on sensitive organisms. The future prospects of polyenes in the treatment of systemic mycoses are considered.
Topics: Amphotericin B; Antifungal Agents; Candida albicans; Cell Wall; Drug Resistance, Microbial; Fungi; Humans; Polyenes; Saccharomyces cerevisiae
PubMed: 392481
DOI: 10.1136/pgmj.55.647.653 -
Organic Letters Apr 2022The first total synthesis of the abietaquinone methide diterpenoid (-)-3-oxoisotaxodione is reported. The key enabling step is the use of a chiral bicyclic hydrazide as...
The first total synthesis of the abietaquinone methide diterpenoid (-)-3-oxoisotaxodione is reported. The key enabling step is the use of a chiral bicyclic hydrazide as an organocatalyst for the enantioselective polyene cyclization of a ()-polyene substrate to form the -decalin core of the natural product. The α-oxo--quinone methide unit is formed by a two-step oxidation from a phenol, enabling an efficient synthesis of the natural product.
Topics: Biological Products; Cyclization; Diterpenes; Oxidation-Reduction; Polyenes
PubMed: 35311261
DOI: 10.1021/acs.orglett.2c00444 -
Journal of the American Chemical Society Dec 2012A highly enantioselective polycyclization method has been developed using the combination of Lewis acid activation with iridium-catalyzed allylic substitution. This...
A highly enantioselective polycyclization method has been developed using the combination of Lewis acid activation with iridium-catalyzed allylic substitution. This strategy relies on direct use of branched, racemic allylic alcohols and furnishes a diverse and unique set of carbo- and heteropolycyclic ring systems in good yields and ≥99% ee.
Topics: Catalysis; Cyclization; Iridium; Polyenes; Stereoisomerism
PubMed: 23193947
DOI: 10.1021/ja310386m -
Scientific Reports Sep 2018Polyene macrolides such as nystatin A1 and amphotericin B belong to a large family of very valuable antifungal polyketide compounds typically produced by soil...
Polyene macrolides such as nystatin A1 and amphotericin B belong to a large family of very valuable antifungal polyketide compounds typically produced by soil actinomycetes. Recently, nystatin-like Pseudonocardia polyene (NPP) A1 has been identified as a unique disaccharide-containing tetraene antifungal macrolide produced by Pseudonocardia autotrophica. Despite its significantly increased water solubility and decreased hemolytic activity, its antifungal activity remains limited compared with that of nystatin A1. In this study, we developed NPP B1, a novel NPP A1 derivative harboring a heptaene core structure, by introducing two amino acid substitutions in the putative NADPH-binding motif of the enoyl reductase domain in module 5 of the NPP A1 polyketide synthase NppC. The low level NPP B1 production yield was successfully improved by eliminating the native plasmid encoding a polyketide biosynthetic gene cluster present in P. autotrophica. In vitro and in vivo antifungal activity and toxicity studies indicated that NPP B1 exhibited comparable antifungal activity against Candida albicans and was less toxic than the most potent heptaene antifungal, amphotericin B. Moreover, NPP B1 showed improved pharmacokinetic parameters compared to those of amphotericin B, suggesting that NPP B1 could be a promising candidate for development into a pharmacokinetically improved and less-toxic polyene antifungal antibiotic.
Topics: Actinobacteria; Amino Acid Sequence; Amino Acid Substitution; Animals; Antifungal Agents; Binding Sites; Candida albicans; Candidiasis; Disaccharides; Fungal Proteins; Gene Expression; Macrolides; Male; Metabolic Engineering; Mice; Mice, Inbred ICR; Microbial Sensitivity Tests; NADP; Nystatin; Plasmids; Polyenes; Polyketide Synthases; Sequence Alignment; Structure-Activity Relationship; Survival Analysis
PubMed: 30206268
DOI: 10.1038/s41598-018-31801-y -
Biochemistry Jul 2018Burkholderia thailandensis produces an impressive array of secondary metabolites, most with yet unknown targets. One of these metabolites is thailandamide, a linear...
Burkholderia thailandensis produces an impressive array of secondary metabolites, most with yet unknown targets. One of these metabolites is thailandamide, a linear polyene natural product that is constitutively synthesized by the corresponding tha gene cluster. Using broad bioactivity screens, we observed strong yet selective antibacterial activity by thailandamide against Gram-positive and cell wall-weakened Gram-negative bacteria. Bacterial cytological profiling and comparison with 10 antibiotics with known modes of action revealed a unique profile for thailandamide, suggesting a distinct mechanism of inhibition. To address the target of the drug, we obtained resistant mutants of Bacillus subtilis and mapped the resistant phenotype to accA, the product of which catalyzes the first committed step in fatty acid biosynthesis. Interestingly, the tha gene cluster encodes an accA homologue with a similar amino acid substitution. Heterologous expression showed that it confers resistance to otherwise susceptible Escherichia coli cultures, indicating that it provides immunity to thailandamide-producing B. thailandensis cells. Aside from moiramide B and andrimid, thailandamide represents only the second class of natural products that inhibits bacterial growth by targeting AccA/AccD.
Topics: Anti-Bacterial Agents; Bacterial Infections; Biological Products; Biosynthetic Pathways; Burkholderia; Fatty Acids; Gram-Negative Bacteria; Gram-Positive Bacteria; Humans; Models, Molecular; Polyenes; Polyketides
PubMed: 29975047
DOI: 10.1021/acs.biochem.8b00678 -
Tanpakushitsu Kakusan Koso. Protein,... 1977
Review
Topics: Amphotericin B; Antifungal Agents; Cell Membrane; Cell Membrane Permeability; Chemical Phenomena; Chemistry; Epidermophyton; Ergosterol; Filipin; Membrane Lipids; Membranes, Artificial; Models, Molecular; Nystatin; Polyenes; Spectrophotometry, Ultraviolet; Triterpenes
PubMed: 322216
DOI: No ID Found -
Biochimie Jan 1989From permeability experiments carried out with series of amphotericin B derivatives in both biological and model membranes, it was concluded that derivatives, whose...
From permeability experiments carried out with series of amphotericin B derivatives in both biological and model membranes, it was concluded that derivatives, whose carboxyl group at the C18 position is blocked by substitution, are much more efficient at inducing permeability in ergosterol-containing than in cholesterol-containing membranes, whereas derivatives whose carboxyl group is free and ionizable are equally efficient in both membranes types. Binding measurements on erythrocyte membranes showed that all amphotericin B derivatives simply partition between membrane lipids and aqueous medium, according to their lipid solubility. There is no relationship between binding and efficiency in inducing permeability. Permeability studies carried out on lipidic vesicles containing various sterols showed that: 1) derivatives having their carboxyl free induced permeability of the 'channel' type, regardless of the sterol present, and no detectable permeability in sterol-free membranes; 2) derivatives whose carboxyl group is blocked induce channels only in membranes containing ergosterol or sterols having an alkyl side chain identical to that of ergosterol. In the presence of other sterols or in sterol-free membranes, their ionophoric activity is poor and always of the 'mobile-carrier' type. A model of polyene-sterol interaction is proposed, accounting for the data obtained with both biological and model membranes.
Topics: Amphotericin B; Anti-Bacterial Agents; Binding, Competitive; Cell Membrane Permeability; Cholesterol; Ergosterol; Erythrocyte Membrane; Humans; Ionophores; Ions; Magnetic Resonance Spectroscopy; Membranes, Artificial; Polyenes
PubMed: 2497796
DOI: 10.1016/0300-9084(89)90129-6 -
Langmuir : the ACS Journal of Surfaces... Mar 2015Three ceramide analogues have been synthesized, with sphingosine-like chains containing five conjugated double bonds. Pentaene I has an N-palmitoyl acyl chain, while the...
Three ceramide analogues have been synthesized, with sphingosine-like chains containing five conjugated double bonds. Pentaene I has an N-palmitoyl acyl chain, while the other two pentaenes contain also a doxyl radical, respectively, at C5 (Penta5dox) and at C16 (Penta16dox) positions of the N-acyl chain. Pentaene I maximum excitation and emission wavelengths in a phospholipid bilayer are 353 and 478 nm, respectively. Pentaene I does not segregate from the other lipids in the way natural ceramide does, but rather mixes with them in a selective way according to the lipid phases involved. Fluorescence confocal microscopy studies show that when lipid domains in different physical states coexist, Pentaene I emission is higher in gel than in fluid domains, and in liquid-ordered than in liquid-disordered areas. Electron paramagnetic resonance of the pentaene doxyl probes confirms that these molecules are sensitive to the physical state of the bilayer. Calorimetric and fluorescence quenching experiments suggest that the lipids under study orient themselves in lipid bilayers with their polar moieties located at the lipid-water interface. The doxyl radical in the N-acyl chain quenches the fluorescence of the pentaene group when in close proximity. Because of this property, Penta16dox can detect gel-fluid transitions in phospholipids. The availability of probes for lipids in the gel phase is important in view of novel evidence for the existence of gel microdomains in cell membranes.
Topics: Ceramides; Fluorescence; Fluorescent Dyes; Molecular Structure; Polyenes
PubMed: 25658138
DOI: 10.1021/la505017x -
Spectrochimica Acta. Part A, Molecular... Dec 2022Mathematically describing the length-dependence of vibrational fingerprints of polyenes is challenging, yet crucial in understanding and predicting polyene-associated...
Mathematically describing the length-dependence of vibrational fingerprints of polyenes is challenging, yet crucial in understanding and predicting polyene-associated molecular properties of industrially-important and vital substances. To this end, we develop an analytical relationship between the wavenumbers ν∼ of the Raman-active CC stretching mode in polyene sequences (CHCH)n and the polyene length (n) using classical mechanics laws. Noteworthy, this relationship is derived from Newton's equations instead of regression approximations and validated against experimental data for degraded polyvinyl chloride (PVC), t-butyl end-capped all-trans polyenes, β-carotenes, and carotenoids. Furthermore, given this fundamental tool, we carefully re-examined or validated the up-to-now applied empirical tools; we find that: (i) A phenomenological exponential regression function ν~=1461+151.2×exp-0.07808n proves fairly suitable for describing polyenes with lengths below 24 in degraded PVC. (ii) The derived analytical relationship agrees more closely with a long-established reciprocal-length regression function ν~=1459+720/n+1 for describing carotenoids. Moreover, extensive DFT calculation results on all-trans polyenes H(CHCH)H (n = 3-30) and polyenes end-capped with terminal vinyl chloride oligomers agree with experiment for shorter polyenes and are similar, showing that complicated calculations of ν∼ for infinite degraded PVC chains reduce to the calculations on finite polyene sequences. Noteworthy, unlike other polyene length-determination tools, the proposed analytical polyene length-determination based on intrinsic physical properties could well prove to be an even more versatile tool, as it comes with the added potential for determining or correcting the elasticity constants of carbon bonds in polyene chains.
Topics: Carotenoids; Polyenes; Polyvinyl Chloride; Vibration
PubMed: 35926286
DOI: 10.1016/j.saa.2022.121653 -
Biochemistry Oct 2021A transmembrane proton gradient is generated and maintained by proton pumps in a cell. Metagenomics studies have recently identified a new category of rhodopsin...
A transmembrane proton gradient is generated and maintained by proton pumps in a cell. Metagenomics studies have recently identified a new category of rhodopsin intermediates between type-1 rhodopsins and heliorhodopsins, named schizorhodopsins (SzRs). SzRs are light-driven inward proton pumps. Comprehensive resonance Raman measurements were conducted to characterize the structure of the retinal chromophore in the unphotolyzed state of four SzRs. The spectra of all four SzRs show that the retinal chromophore is in the all- and 15- configuration and that the Schiff base is protonated. The polyene chain is planar in the center of the retinal chromophore and is twisted in the vicinity of the protonated Schiff base. The protonated Schiff base in the SzRs forms a stronger hydrogen bond than that in outward proton-pumping rhodopsins. We determined that the hydrogen-bonding partner of the protonated Schiff base is not a water molecule but an amino acid residue, presumably an Asp residue in helix G. The present observations provide valuable insights into the inward proton-pumping mechanism of SzRs.
Topics: Archaea; Archaeal Proteins; Hydrogen Bonding; Polyenes; Proton Pumps; Rhodopsins, Microbial; Schiff Bases
PubMed: 34601881
DOI: 10.1021/acs.biochem.1c00529