Burger's Medicinal Chemistry and Drug Discovery, 2003
Microbial sources of natural products are increasingly valued for their chemical diversity and ac... more Microbial sources of natural products are increasingly valued for their chemical diversity and access to biosynthetic pathways. It appears that an incredible repository of untapped microbial life and associated chemical diversity remain to be exploited. Molecular techniques such as “metagenomics” are beginning to provide access to cryptic biosynthetic pathways, which are also revealing new chemistry. Refined libraries of natural products with well-characterized components provide enhanced value as screening sources. These libraries continue to provide new chemical entities that inform biological processes and provide leads for therapeutic agents. There is a renaissance of phenotypic screening that promises to uncover numerous new links between secondary metabolites and their roles in biology. Genomic methods are growing in value as our understanding of biosynthetic processes at the molecular level expands. Screening of DNA sequences for pathways that yield particular chemistries is now a reality for certain types of biosynthetic processes, especially type I polyketide synthases and nonribosomally produced peptides. Keywords: biodiversity; marine actinomycetes; microbial genomics; natural products lead generation; natural products libraries; screening; secondary metabolites
The mechanism of action of sceptrin, an antimicrobial agent isolated from the sponge Agelas mauri... more The mechanism of action of sceptrin, an antimicrobial agent isolated from the sponge Agelas mauritiana, was investigated. Sceptrin has been reported to exhibit antibacterial and antifungal activities. In our studies, sceptrin demonstrated a bacteriostatic rather than bactericidal effect on exponentially growing Escherichia coli cells at the MIC. Under these conditions, the culture produced chains of cells, and incorporation of radio-labelled precursors into DNA, protein, and cell wall was unaffected, whereas incorporation of 3H-uridine into RNA was slightly inhibited. At concentrations higher than the MIC, sceptrin was bactericidal, inhibited the incorporation of all radiolabelled precursors, and induced the formation of unusual spheroplasts. Peptidoglycan turnover in E. coli appeared to be stimulated by sceptrin as demonstrated by a release of diaminopimelic acid-containing high molecular weight material. Subsequent studies of the release of potassium ions from E. coli and the lysis of red blood cells suggested that sceptrin disrupts the cell membranes of both prokaryotic and eukaryotic cells. It is proposed that spheroplasts formation may reflect a cell wall effect that occurs subsequent to membrane damage.
Journal of Industrial Microbiology & Biotechnology, 2003
The possibility of using solid supports and intermittent substrate feeding to manipulate biotrans... more The possibility of using solid supports and intermittent substrate feeding to manipulate biotransformation by fungi was examined, with amoxapine as a model compound. Cunninghamella elegans ATCC 8688a grown as free cells in six-well plates showed 7-hydroxyamoxapine as the major metabolite of amoxapine biotransformation. However, when cells were grown in the presence of activated carbon, N-formyl-7-hydroxyamoxapine was formed as the major
Over the past decade, marine microorganisms have become recognized as an important and untapped r... more Over the past decade, marine microorganisms have become recognized as an important and untapped resource for novel bioactive compounds. The oceans cover greater than 70% of the earth's surface and, taking this into account by volume, represent better than 95% of the biosphere. Given this fact, the oceans present themselves as an unexplored area of opportunity for the discovery of pharmacologically active compounds. In this review, data have been presented to illustrate the diversity of microorganisms living in the sea and the plethora of chemical compounds that have been discovered from them. However, it is important to pursue basic research on the marine environment in order to permit the continued isolation of unique microorganisms. There is still limited knowledge of the physiological requirements of most marine microorganisms, and a greater understanding of their conditions for growth will offer new insights into the complex world of marine microbiology. Clearly, a greater investment in the development of marine biotechnology will produce novel compounds that may contribute significantly toward drug development over the next decade.
Burger's Medicinal Chemistry and Drug Discovery, 2003
Microbial sources of natural products are increasingly valued for their chemical diversity and ac... more Microbial sources of natural products are increasingly valued for their chemical diversity and access to biosynthetic pathways. It appears that an incredible repository of untapped microbial life and associated chemical diversity remain to be exploited. Molecular techniques such as “metagenomics” are beginning to provide access to cryptic biosynthetic pathways, which are also revealing new chemistry. Refined libraries of natural products with well-characterized components provide enhanced value as screening sources. These libraries continue to provide new chemical entities that inform biological processes and provide leads for therapeutic agents. There is a renaissance of phenotypic screening that promises to uncover numerous new links between secondary metabolites and their roles in biology. Genomic methods are growing in value as our understanding of biosynthetic processes at the molecular level expands. Screening of DNA sequences for pathways that yield particular chemistries is now a reality for certain types of biosynthetic processes, especially type I polyketide synthases and nonribosomally produced peptides. Keywords: biodiversity; marine actinomycetes; microbial genomics; natural products lead generation; natural products libraries; screening; secondary metabolites
The mechanism of action of sceptrin, an antimicrobial agent isolated from the sponge Agelas mauri... more The mechanism of action of sceptrin, an antimicrobial agent isolated from the sponge Agelas mauritiana, was investigated. Sceptrin has been reported to exhibit antibacterial and antifungal activities. In our studies, sceptrin demonstrated a bacteriostatic rather than bactericidal effect on exponentially growing Escherichia coli cells at the MIC. Under these conditions, the culture produced chains of cells, and incorporation of radio-labelled precursors into DNA, protein, and cell wall was unaffected, whereas incorporation of 3H-uridine into RNA was slightly inhibited. At concentrations higher than the MIC, sceptrin was bactericidal, inhibited the incorporation of all radiolabelled precursors, and induced the formation of unusual spheroplasts. Peptidoglycan turnover in E. coli appeared to be stimulated by sceptrin as demonstrated by a release of diaminopimelic acid-containing high molecular weight material. Subsequent studies of the release of potassium ions from E. coli and the lysis of red blood cells suggested that sceptrin disrupts the cell membranes of both prokaryotic and eukaryotic cells. It is proposed that spheroplasts formation may reflect a cell wall effect that occurs subsequent to membrane damage.
Journal of Industrial Microbiology & Biotechnology, 2003
The possibility of using solid supports and intermittent substrate feeding to manipulate biotrans... more The possibility of using solid supports and intermittent substrate feeding to manipulate biotransformation by fungi was examined, with amoxapine as a model compound. Cunninghamella elegans ATCC 8688a grown as free cells in six-well plates showed 7-hydroxyamoxapine as the major metabolite of amoxapine biotransformation. However, when cells were grown in the presence of activated carbon, N-formyl-7-hydroxyamoxapine was formed as the major
Over the past decade, marine microorganisms have become recognized as an important and untapped r... more Over the past decade, marine microorganisms have become recognized as an important and untapped resource for novel bioactive compounds. The oceans cover greater than 70% of the earth's surface and, taking this into account by volume, represent better than 95% of the biosphere. Given this fact, the oceans present themselves as an unexplored area of opportunity for the discovery of pharmacologically active compounds. In this review, data have been presented to illustrate the diversity of microorganisms living in the sea and the plethora of chemical compounds that have been discovered from them. However, it is important to pursue basic research on the marine environment in order to permit the continued isolation of unique microorganisms. There is still limited knowledge of the physiological requirements of most marine microorganisms, and a greater understanding of their conditions for growth will offer new insights into the complex world of marine microbiology. Clearly, a greater investment in the development of marine biotechnology will produce novel compounds that may contribute significantly toward drug development over the next decade.
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Papers by Valerie Bernan