Biotransformations of organic compounds mediated by cultures of Aspergillus niger.

Many different organic compounds may be converted by microbial biotransformation to high-value products for the chemical and pharmaceutical industries. This review summarizes the use of strains of Aspergillus niger, a well-known filamentous fungus used in numerous biotechnological processes, for biochemical transformations of organic compounds. The substrates transformed include monocyclic, bicyclic, and polycyclic aromatic hydrocarbons; azaarenes, epoxides, chlorinated hydrocarbons, and other aliphatic and aromatic compounds. The types of reactions performed by A. niger, although not unique to this species, are extremely diverse. They include hydroxylation, oxidation of various functional groups, reduction of double bonds, demethylation, sulfation, epoxide hydrolysis, dechlorination, ring cleavage, and conjugation. Some of the products may be useful as new investigational drugs or chemical intermediates.

Biotransformation of Steroids and Flavonoids by Cultures of Aspergillus niger.

Steroids are derivatives of the triterpenoid squalene, containing three fused cyclohexane rings and a cyclopentane ring, and flavonoids are derivatives of L-phenylalanine, containing two aromatic rings joined by a three-carbon bridge that may form part of a heterocyclic ring. A great variety of steroids and flavonoids are produced by plants, and many additional steroids are produced by animals or fungi. Because these compounds have many nutritional and pharmaceutical values, and many of them cannot be produced by chemical synthesis, biotechnological processes are being developed that use cultures of Aspergillus niger and other fungi to transform steroids and flavonoids to a variety of metabolites. These biochemical reactions, including hydroxylation, dehydrogenation, O-methylation, demethylation, cleavage of rings, epoxide hydrolysis, double bond reduction, and others, may be used for the production of higher-value compounds.

Transformation of saturated nitrogen-containing heterocyclic compounds by microorganisms.

The saturated nitrogen-containing heterocyclic compounds include many drugs and compounds that may be used as synthons for the synthesis of other pharmacologically active substances. The need for new derivatives of saturated nitrogen-containing heterocycles for organic synthesis, biotechnology and the pharmaceutical industry, including optically active derivatives, has increased interest in microbial synthesis. This review provides an overview of microbial technologies that can be valuable to produce new derivatives of saturated nitrogen-containing heterocycles, including hydroxylated derivatives. The chemo-, regio- and enantioselectivity of microbial processes can be indispensable for the synthesis of new compounds. Microbial processes carried out with fungi, including Beauveria bassiana, Cunninghamella verticillata, Penicillium simplicissimum, Aspergillus niger and Saccharomyces cerevisiae, and bacteria, including Pseudomonas sp., Sphingomonas sp. and Rhodococcus erythropolis, biotransform many substrates efficiently. Among the biological activities of saturated nitrogen-containing heterocyclic compounds are antimicrobial, antitumor, antihypertensive and anti-HIV activities; some derivatives are effective for the treatment and prevention of malaria and trypanosomiasis, and others are potent glycosidase inhibitors.

Microbial transformations of antimicrobial quinolones and related drugs.

The quinolones are an important group of synthetic antimicrobial drugs used for treating bacterial diseases of humans and animals. Microorganisms transform antimicrobial quinolones (including fluoroquinolones) and the pharmacologically related naphthyridones, pyranoacridones, and cinnolones to a variety of metabolites. The biotransformation processes involve hydroxylation of methyl groups; hydroxylation of aliphatic and aromatic rings; oxidation of alcohols and amines; reduction of carboxyl groups; removal of methyl, carboxyl, fluoro, and cyano groups; addition of formyl, acetyl, nitrosyl, and cyclopentenone groups; and cleavage of aliphatic and aromatic rings. Most of these reactions greatly reduce or eliminate the antimicrobial activity of the quinolones.

Microbial transformation of azaarenes and potential uses in pharmaceutical synthesis.

Pyridine, quinoline, acridine, indole, carbazole, and other heterocyclic nitrogen-containing compounds (azaarenes) can be transformed by cultures of bacteria and fungi to produce a variety of new derivatives, many of which have biological activity. In many cases, the microbial biotransformation processes are regio- and stereoselective so that the transformation products may be useful for the synthesis of new candidate drugs.

Microbial transformation of antimalarial terpenoids.

The fungal and bacterial transformation of terpenoids derived from plant essential oils, especially the sesquiterpenoid artemisinin from Artemisia annua, has produced several new candidate drugs for the treatment of malaria. Obtaining new derivatives of terpenoids, including artemisinin derivatives with increased antimalarial activity, is an important goal of research in microbial biotechnology and medicinal chemistry.

Microbial transformation of artemisinin to 5-hydroxyartemisinin by Eurotium amstelodami and Aspergillus niger.

Transformation of the anti-malarial drug artemisinin by the fungi Eurotium amstelodami and Aspergillus niger were investigated. Cultures were grown in sucrose/malt broth with artemisinin for 14 days and extracted with ethyl acetate. Extracts were characterized by liquid chromatography. Two metabolites from each fungal extract were isolated and identified using mass spectrometry and nuclear magnetic resonance. 5Beta-hydroxyartemisinin and 7beta-hydroxyartemisinin were isolated in 63 and 32% yields, respectively, from the extract of E. amstelodami, and 80 and 19%, respectively, from the extract of A. niger.

Hydroxylation of 10-deoxoartemisinin by Cunninghamella elegans.

The microbial metabolism of 10-deoxoartemisinin (1), a derivative of the antimalarial drug artemisinin, was investigated. Various strains of fungi were investigated for their ability to transform 1. Of these microorganisms, only Cunninghamella elegans was capable of transforming 1 to 5beta-hydroxy-10-deoxoartemisinin (2), 4alpha-hydroxy-1,10-deoxoartemisinin (3), and 7beta-hydroxy-10-deoxoartemisinin (4). The metabolites 2 and 4 retained an intact peroxide group and are therefore useful scaffolds for synthetic modification in the search for new antimalarial agents.

Hydroxylation of 10-deoxoartemisinin to 15-hydroxy-10-deoxoartemisinin by Aspergillus niger.

The microbial hydroxylation of 10-deoxoartemisinin was investigated with the aim of obtaining preparative yields of hydroxy derivatives. During 14 d at 28 degrees C and pH 6.5 Aspergillus niger transformed 10-deoxoartemisinin (500 mg l(-1)) to 15-hydroxy-10-deoxoartemisinin (26%) and 7beta-hydroxy-10-deoxoartemisinin (69%).

Transformation of cinoxacin by Beauveria bassiana.

The ability of the fungus Beauveria bassiana ATCC 7159 to transform the antibacterial agent cinoxacin was investigated. Cultures in sucrose-peptone broth were dosed with cinoxacin, grown for 20 days, and then extracted with ethyl acetate. Two metabolites were detected and purified by high-performance liquid chromatography. The major metabolite was identified by mass and proton nuclear magnetic resonance spectra as 1-ethyl-1,4-dihydro-3-(hydroxymethyl)[1,3]dioxolo[4,5-g]cinnolin-4-one and the minor metabolite was identified as 1-ethyl-1,4-dihydro-6,7-dihydroxy-3-(hydroxymethyl)cinnolin-4-one. B. bassiana also reduced quinoline-3-carboxylic acid to 3-(hydroxymethyl)quinoline.

Formation of conjugates from ciprofloxacin and norfloxacin in cultures of Trichoderma viride.

The formation of conjugates from two antibacterial fluoroquinolone drugs, ciprofloxacin and norfloxacin, was observed in cultures of Trichoderma viride that had been grown in sucrose-peptone broth and extracted 16 d after dosing with the drugs. Both conjugates were purified by high-performance liquid chromatography and found to be optically active. They were identified by mass and proton nuclear magnetic resonance spectra as 4-hydroxy-3-oxo-4-vinylcyclopent-1-enyl ciprofloxacin and 4-hydroxy-3-oxo-4-vinylcyclopent-1-enyl norfloxacin. The transformation of veterinary fluoroquinolones in the presence of fungi may have ecological significance.