This contribution is a completely updated and expanded version of the four prior analogous reviews that were published in this journal in 1997, 2003, 2007, and 2012. In the case of all approved therapeutic agents, the time frame has been extended to cover the 34 years from January 1, 1981, to December 31, 2014, for all diseases worldwide, and from 1950 (earliest so far identified) to December 2014 for all approved antitumor drugs worldwide. As mentioned in the 2012 review, we have continued to utilize our secondary subdivision of a “natural product mimic”, or “NM”, to join the original primary divisions and the designation “natural product botanical”, or “NB”, to cover those botanical “defined mixtures” now recognized as drug entities by the U.S. FDA (and similar organizations). From the data presented in this review, the utilization of natural products and/or their novel structures, in order to discover and develop the final drug entity, is still alive and well. For example, in the area of cancer, over t...

Natural Products as Sources of New Drugs from 1981 to 2014

Antibiotics in the aquatic environment - A review - Part II

3.3.1. Potential of the “Metagenome” 3016 3.3.2. Cryptic Clusters in Bacteria and Fungi 3016 3.3.3. Cyanophytes 3017 3.3.4. Marine Microbes (Non-Cyanophytes) 3018 3.3.5. Extremophiles 3018 3.3.6. Microbial Symbionts 3019 3.3.7. Plant Endophytes 3020 3.3.8. Combinatorial Biosynthesis 3020 4. Development of Drugs from Natural Products 3020 4.1. Synthesis Based on Natural Products 3021 4.1.1. Derivatization and Semisynthesis 3021 4.1.2. Total Synthesis 3021 4.1.3. Diverted Total Synthesis 3021 4.2. Natural Product-Inspired Combinatorial Synthesis 3022

Impact of natural products on developing new anti-cancer agents

Occurrence and fate of emerging contaminants in municipal wastewater treatment plants from different geographical regions-a review.

Around all human activity, there are zones of pollution with pesticides, heavy metals, pharmaceuticals, personal care products and the microorganisms associated with human waste streams and agriculture. This diversity of pollutants, whose concentration varies spatially and temporally, is a major challenge for monitoring. Here, we suggest that the relative abundance of the clinical class 1 integron-integrase gene, intI1, is a good proxy for pollution because: (1) intI1 is linked to genes conferring resistance to antibiotics, disinfectants and heavy metals; (2) it is found in a wide variety of pathogenic and nonpathogenic bacteria; (3) its abundance can change rapidly because its host cells can have rapid generation times and it can move between bacteria by horizontal gene transfer; and (4) a single DNA sequence variant of intI1 is now found on a wide diversity of xenogenetic elements, these being complex mosaic DNA elements fixed through the agency of human selection. Here we review the literature examining the relationship between anthropogenic impacts and the abundance of intI1, and outline an approach by which intI1 could serve as a proxy for anthropogenic pollution.

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Using the class 1 integron-integrase gene as a proxy for anthropogenic pollution

The pentacyclic quinoline alkaloid camptothecin (1) is a potent antineoplastic agent. Two of its analogues, 9-methoxycamptothecin (2) and 10-hydroxycamptothecin (3), exhibit similar potency but do not have the potential therapeutic drawbacks produced by unmodified 1. We have established methodology for the isolation and unequivocal identification and characterization of a novel endophytic fungus isolated from the inner bark of the medicinal plant Camptotheca acuminata, which produced 1-3 in rich mycological medium (Sabouraud dextrose broth), under shake-flask fermentation conditions. The fungus was identified by its morphology and authenticated by ITS analysis (ITS1 and ITS2 regions and the intervening 5.8S rDNA region). Camptothecin (1) and its analogues were identified by 1H NMR spectroscopy and LC-HRMS and confirmed by comparison with authentic standards. The production pattern of the metabolites over seven successive subculture generations of this endophyte was studied. A sharp attenuation in the production of 1 and 2 was observed from the first- through to the seventh-generation subculture. Therefore, these results offer a caution as to the possibility of using endophytic fungi as alternate sources of plant secondary metabolite production. Further studies have been initiated on the analysis of the upstream metabolic intermediates to understand the steps at which the production of the metabolites in question is constrained.

An endophytic fungus from Camptotheca acuminata that produces camptothecin and analogues

For the first time, an endophytic fungus has been isolated from the stems of the medicinal herb Hypericum perforatum (St. John's Wort). The fungus produced the napthodianthrone derivative hypericin ( 1) in rich mycological medium (potato dextrose broth) under shake flask and bench scale fermentation conditions. Emodin ( 2) was also produced simultaneously by the fungus under the same culture conditions. We propose 2 as the main precursor in the microbial metabolic pathway to 1. The fungus was identified by morphology and authenticated by 28S (LSU) rDNA sequencing. Compounds 1 and 2 were identified by LC-HRMS, LC-MS/MS, and LC-HRMS/MS and confirmed by comparison with authentic standards. In bioassays with a panel of laboratory standard pathogenic control strains, including fungi and bacteria, both fungal 1 and 2 possessed antimicrobial activity comparable to authentic standards. This endophytic fungus has significant scientific and industrial potential to meet the pharmaceutical demands for 1 in a cost-effective, easily accessible, and reproducible way.

An endophytic fungus from Hypericum perforatum that produces hypericin.

Sorption and desorption of sulfadiazine in soil and soil-manure systems.

Occurrence of diclofenac and selected metabolites in sewage effluents.

Fungal endophytes inhabit healthy tissues of all terrestrial plant taxa studied and occasionally produce host-specific compounds. We recently isolated an endophytic fungus, Fusarium solani, from Camptotheca acuminata, capable of biosynthesizing camptothecin (CPT, 1), but this capability substantially decreased on repeated subculturing. The endophyte with an impaired 1 biosynthetic capability was artificially inoculated into the living host plants and then recovered after colonization. Although the host-endophyte interaction could be reconstituted, biosynthesis of 1 could not be restored. Using a homology-based approach and high-precision isotope-ratio mass spectrometry (HP-IRMS), a cross-species biosynthetic pathway is proposed where the endophyte utilizes indigenous G10H (geraniol 10-hydroxylase), SLS (secologanin synthase), and TDC (tryptophan decarboxylase) to biosynthesize precursors of 1. However, the endophyte requires host STR (strictosidine synthase) in order to condense the nitrogen-containing moiety (tryptamine, 2) with the carbon-containing moiety (secologanin, 3) to form strictosidine (4) and complete the biosynthesis of 1. Biosynthetic genes of 1 in the seventh subculture generation of the endophyte revealed random and unpredictable nonsynonymous mutations. These random base substitutions led to dysfunction at the amino acid level. The controls, Top1 gene and rDNA, remained intact over subculturing, revealing that instability of biosynthetic genes of 1 was not reflected in the primary metabolic processes and functioning of the housekeeping genes. The present results reveal the causes of decreased production of 1 on subculturing, which could not be reversed by host-endophyte reassociation.

Effect of artificial reconstitution of the interaction between the plant Camptotheca acuminata and the fungal endophyte Fusarium solani on camptothecin biosynthesis.

Sebastian Zühlke

Papers

An endophytic fungus from Camptotheca acuminata that produces camptothecin and analogues

An endophytic fungus from Hypericum perforatum that produces hypericin.

Sorption and desorption of sulfadiazine in soil and soil-manure systems.

Occurrence of diclofenac and selected metabolites in sewage effluents.

Effect of artificial reconstitution of the interaction between the plant Camptotheca acuminata and the fungal endophyte Fusarium solani on camptothecin biosynthesis.