Abstract
This study was designed to identify and investigate bioactive natural product compounds that alter the cellular shape of the fission yeast Schizosaccharomyces pombe and induce a “rounded” or “small” cellular morphological phenotype. Bioassays using a range of antifungal agents against a multidrug-sensitive fission yeast strain, SAK950 showed that many induced a “rounded” phenotype. We then investigated whether 46 of the actinomycete strains identified in our previous study as inducing a similar phenotype produced antifungal agents of similar classes. We show that five of the strains produced streptothricin and that 26 strains produced polyenes, including fungichromin, filipin and candicidin, the last of which was produced by 24 strains. A taxonomic study of the strains indicated that the majority of the candicidin only producers were Streptomyces hydrogenans and S. albidoflavus whilst those that additionally produced streptothricin were related to S. enissocaesilis. A follow-up study to investigate the natural products made by related strains indicated that they followed a similar pattern. The identification of several compounds from the actinomycete strains similar to the antifungal agents initially tested confirm the validity of an approach using the S. pombe morphological phenotype and actinomycete taxonomy as a predictive tool for natural product identification.Graphic
Highlights
Actinomycetes are soil dwelling, filamentous bacteria which have a complex life-cycle, often comprising differentiation and sporulation
We did not observe this phenotype during the screen of the actinomycete strain collection it is reminiscent of the “cell wall” phenotype induced by the Streptomyces griseus strain 5307 (1B)
It is not surprising that they induce a similar phenotype in S. pombe, as they all act via the same target molecule
Summary
Actinomycetes are soil dwelling, filamentous bacteria which have a complex life-cycle, often comprising differentiation and sporulation. In our recent study we described a novel screen for bioactive natural compounds produced by soil dwelling actinomycete bacteria using a microscopy-based approach to determine their effect on S. pombe cellular morphology, to identify chemical entities affecting these processes. We successfully identified a large number of actinomycete bacterial strains which produced bioactive compounds, which we classified according to their ability to induce eight major phenotypes in S. pombe The success of this new screening approach has been validated by us identifying several known natural products (cycloheximide, streptonigrin, leptomycin) which induce S. pombe phenotypes which can be explained by their known modes of action. The results of our screen indicated that it should be possible to use the Schizosaccharomyces pombe phenotypes induced by compounds as guides to identifying natural product/s, which inhibit a particular cellular target, or molecular mechanism To test this we designed a follow-up study to look at the S. pombe phenotypes induced by a number of known, commercially available antifungal agents. It was hoped the results would allow us to predict the cellular target and/or compound type of as yet unknown natural products identified in the screen, and so focus research on particular actinomycete strains producing classes of natural product which are of interest to us
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