Since the discovery over 60 years ago of fluorocortisone’s biological properties (9-α-Fluoro derivatives of cortisone and hydrocortisone; Fried J and Sabo EF, J Am Chem Soc 76: 1455–1456, 1954), the ...number of fluorinated drugs has steadily increased. With the improvement in synthetic methodologies, this trend is likely to continue and will lead to the introduction of new fluorinated substituents into pharmaceutical compounds. Although the biotransformation of organofluorine compounds by microorganisms has been well studied, specific investigations on fluorinated drugs are relatively few, despite the increase in the number and variety of fluorinated drugs that are available. The strength of the carbon-fluorine bond conveys stability to fluorinated drugs; thus, they are likely to be recalcitrant in the environment or may be partially metabolized to a more toxic metabolite. This review examines the research done on microbial biotransformation and biodegradation of fluorinated drugs and highlights the importance of understanding how microorganisms interact with this class of compound from environmental, clinical and biotechnological perspectives.
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CEKLJ, DOBA, EMUNI, FZAB, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Several wild type and recombinant microorganisms can transform drugs to the equivalent human metabolites. Fungi, such as
Cunninghamella
spp., and
Streptomyces
bacteria express cytochrome P450 (CYP) ...enzymes that enable analogous phase I (oxidative) reactions with a wide range of drugs. The gene encoding the bifunctional CYP102A1 in
Bacillus megaterium
can be expressed easily in
E. coli
, and extensive mutagenesis experiments have generated numerous variants that can produce human drug metabolites. Additionally, human CYP isoforms have been expressed in various hosts. The application of microbial CYPs to the production of human drug metabolites is reviewed, and additional applications in the field of drug development are considered.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Cunninghamella elegans
is a well-studied fungus that biotransforms a range of xenobiotics owing to impressive cytochrome P450 (CYP) activity. In this paper, we report the biotransformation of 6:2 ...fluorotelomer alcohol (6:2 FTOH) by the fungus, yielding a range of fluorinated products that were detectable by fluorine-19 nuclear magnetic resonance spectroscopy (
19
F NMR), gas chromatography-mass spectrometry (GC–MS) and liquid chromatography-mass spectrometry (LC–MS). Upon incubation with the pre-grown cultures, the substrate (100 mg/L) was completely consumed within 48 h, which is faster biotransformation than other fungi that have hitherto been studied. The main metabolite formed was the 5:3 fluorotelomer carboxylic acid (5:3 FTCA), which accumulated in the culture supernatant. When the cytochrome P450 inhibitor 1-aminobenzotriazole was included in the culture flasks, there was no biotransformation of 6:2 FTOH, indicating that these enzymes are key to the catalysis. Furthermore, when exogenous 5:3 FTCA was added to the fungus, the standard biotransformation of the drug flurbiprofen was inhibited, strongly suggesting that the main fluorotelomer alcohol biotransformation product inhibits CYP activity and accounts for its accumulation.
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CEKLJ, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Fengycins are cyclic lipo-depsipeptides produced by Bacillus spp. that display potent antifungal properties but are chemically unstable. This instability has meant that no total synthesis of any ...fengycin has been published. Here we report the synthesis of fengycin A analogues that display enhanced antifungal properties and chemical stability under both basic and acidic conditions. The analogues prepared also demonstrate that the fengycin core structure can be modified and simplified without the loss of antifungal activity.
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IJS, KILJ, NUK, PNG, UL, UM
In contrast to yeast biofilms, those of filamentous fungi are relatively poorly understood, in particular with respect to their regulation. Cunninghamella elegans is a filamentous fungus that is of ...biotechnological interest as it catabolises drugs and other xenobiotics in an analogous manner to animals; furthermore, it can grow as a biofilm enabling repeated batch biotransformations. Precisely how the fungus switches from planktonic to biofilm growth is unknown and the aim of this study was to shed light on the possible mechanism of biofilm regulation. In dimorphic yeasts, alcohols such as tyrosol and 2-phenylethanol are known to control the yeast-to-hypha switch, and a similar molecule might be involved in regulating biofilm in C. elegans. Gas chromatography-mass spectrometry analysis of crude ethyl acetate extracts from supernatants of 72 h planktonic and biofilm cultures revealed 3-hydroxytyrosol as a prominent metabolite. Further quantification revealed that the amounts of the compound in planktonic cultures were substantially higher (>10-fold) than in biofilm cultures. In the presence of exogenous 3-hydroxytyrosol the growth of aerial mycelium was inhibited, and there was selective inhibition of biofilm when it was added to culture medium. There was no biotransformation of the compound when it was added to 72 h-old cultures, in contrast to the related compounds tyrosol and 2-phenylethanol, which were oxidised to a number of products. Therefore, we propose that 3-hydroxytyrosol is a new signalling molecule in fungi, which regulates biofilm growth.
•3-Hydroxytyrosol is a novel signalling molecule to regulate fungal biofilm growth.•Planktonic cultures have higher concentrations of the metabolite.•Cunninghamella elegans biofilm growth is selectively inhibited by 3-hydroxytyrosol.•2-Phenylethanol and tyrosol inhibit planktonic and biofilm growth of C. elegans.•3-Hydroxytyrosol is not biotransformed by the fungus.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Fluoxetine (FLX) is a blockbuster drug with annual sales in the billions of dollars. Its widespread use has resulted in its detection in water courses, where it impacts aquatic life. Investigations ...on the biodegradation of FLX by microorganisms are important, since augmentation of secondary wastewater treatment by an effective degrader may be one method of improving the drug’s removal. In this paper, we demonstrate that common environmental bacteria can use FLX as a sole carbon and energy source. Investigations into the metabolites formed using fluorine-19 nuclear magnetic resonance spectroscopy (
19
F NMR) and gas chromatography–mass spectrometry indicated that the drug was initially hydrolysed to yield 4-(trifluoromethyl)phenol (TFMP) and 3-(methylamino)-1-phenylpropan-1-ol. Since the fluorometabolite accumulated, the bacteria presumably used the latter compound for carbon and energy. Further growth studies revealed that TFMP could also be used as a sole carbon and energy source and was most likely catabolised via
meta
-cleavage, since semialdehyde products were detected in culture supernatants. The final products of the degradation pathway were trifluoroacetate and fluoride ion; the former is a dead-end product and was not further catabolised. Fluoride ion most likely arises owing to spontaneous defluorination of the
meta
-cleavage products that were shown to be photolabile.
Key points
•
Bacteria can use FLX and TFMP as sole carbon and energy sources for their growth.
•
Biodegradation produces fluorometabolites that were detected by
19
F NMR and GC–MS.
•
Trifluoroacetic acid and fluoride ion were identified as end products.
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CEKLJ, DOBA, EMUNI, FZAB, GEOZS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Three peptides comprising mono-, di-, and tri-fluoroethylglycine (MfeGly, DfeGly, and TfeGly) residues alternating with lysine were digested by readily available proteases (elastase, bromelain, ...trypsin, and proteinase K). The degree of degradation depended on the enzyme employed and the extent of fluorination. Incubation of the peptides with a microbial consortium from garden soil resulted in degradation, yielding fluoride ions. Further biodegradation studies conducted with the individual fluorinated amino acids demonstrated that the degree of defluorination followed the sequence MfeGly > DfeGly > TfeGly. Enrichment of the soil bacteria employing MfeGly as a sole carbon and energy source resulted in the isolation of a bacterium, which was identified as Serratia liquefaciens. Cell-free extracts of this bacterium enzymatically defluorinated MfeGly, yielding fluoride ion and homoserine. In silico analysis of the genome revealed the presence of a gene that putatively codes for a dehalogenase. However, the low overall homology to known enzymes suggests a potentially new hydrolase that can degrade monofluorinated compounds. 19F NMR analysis of aqueous soil extracts revealed the unexpected presence of trifluoroacetate, fluoride ion, and fluoroacetate. Growth of the soil consortium in tryptone soya broth supplemented with fluoride ions resulted in fluoroacetate production; thus, bacteria in the soil produce and degrade organofluorine compounds.
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IJS, KILJ, NUK, PNG, UL, UM
Introduction: Fluorine's unique physicochemical properties make it a key element for incorporation into pharmacologically active compounds. Its presence in a drug can alter a number of ...characteristics that affect ADME-Tox, which has prompted efforts at improving synthetic fluorination procedures.Areas covered: This review describes the influence of fluorine on attributes such as potency, lipophilicity, metabolic stability and bioavailablility and how the effects observed are related to the physicochemical characteristics of the element. Examples of more recently used larger scale synthetic methods for introduction of fluorine into drug leads are detailed and the potential for using biological systems for fluorinated drug production is discussed.Expert opinion: The synthetic procedures for carbon-fluorine bond formation largely still rely on decades-old technology for the manufacturing scale and new reagents and methods are required to meet the demands for the preparation of structurally more complex drugs. The improvement of in vitro and computational methods should make fluorinated drug design more efficient and place less emphasis on approaches such as fluorine scanning and animal studies. The introduction of new fluorinated drugs, and in particular those that have novel fluorinated functional groups, should be accompanied by rigorous environmental assessment to determine the nature of transformation products that may cause ecological damage.
Fungi have been extensively studied for their capacity to biotransform a wide range of natural and xenobiotic compounds. This versatility is a reflection of the broad substrate specificity of fungal ...enzymes such as laccases, peroxidases and cytochromes P450, which are involved in these reactions. This review gives an account of recent advances in the understanding of fungal metabolism of drugs and pollutants such as dyes, agrochemicals and per- and poly-fluorinated alkyl substances (PFAS), and describes the key enzymes involved in xenobiotic biotransformation. The potential of fungi and their enzymes in the bioremediation of polluted environments and in the biocatalytic production of important compounds is also discussed.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
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