Abstract
Marine-derived bacteria and fungi are promising sources of novel bioactive compounds that are important for drug discovery programs. However, as encountered in terrestrial microorganisms there is a high rate of redundancy that results in the frequent re-discovery of known compounds. Apparently only a part of the biosynthetic genes that are harbored by fungi and bacteria are transcribed under routine laboratory conditions which involve cultivation of axenic microbial strains. Many biosynthetic genes remain silent and are not expressed in vitro thereby seriously limiting the chemical diversity of microbial compounds that can be obtained through fermentation. In contrast to this, co-cultivation (also called mixed fermentation) of two or more different microorganisms tries to mimic the ecological situation where microorganisms always co-exist within complex microbial communities. The competition or antagonism experienced during co-cultivation is shown to lead to a significantly enhanced production of constitutively present compounds and/or to an accumulation of cryptic compounds that are not detected in axenic cultures of the producing strain. This review highlights the power of co-cultivation for increasing the chemical diversity of bacteria and fungi drawing on published studies from the marine and from the terrestrial habitat alike.
Highlights
Marine macroorganisms are already firmly established as sources of new drugs for the treatment of cancer and for other malignancies such as chronic pain
In order to determine the gene regulating mechanism present in S. rapamycinicus, A. nidulans was monitored by qRT-PCR, while being incubated either with the cell-free bacterial broth, withculture-derived extracts, with heat killed bacteria or with living bacteria that were kept in a dialysis tube and were physically separated from the fungus
Co-cultivation is expected in the future to routinely complement other experimental approaches that likewise aim at diversifying secondary compound production by microorganisms such as mutagenesis [23,47], the OSMAC approach [23] or treatment of microbes with epigenetic modifiers [24] to name just a few
Summary
Marine macroorganisms are already firmly established as sources of new drugs for the treatment of cancer and for other malignancies such as chronic pain. Several strategies exist that try to overcome these limitations during fermentation of microbes These include among others the OSMAC approach where promising strains are cultured in a variety of media and under different culture regimes in order to maximize the diversity of compounds produced [23], in addition to epigenetic modifications. Recent studies conducted with the fungus Aspergillus nidulans when challenged by Streptomyces rapamycinicus shed for the first time light on the molecular basis of induction of silent fungal biosynthetic gene clusters during co-cultivation [45,46,47] These studies will certainly prove helpful for natural product chemists and molecular microbiologists who are trying to unravel the interspecies cross talk of marine-derived microorganisms in the future
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