Amycolatopsins A–C: antimycobacterial glycosylated polyketide macrolides from the Australian soil Amycolatopsis sp. MST-108494

Abstract

A southern Australian soil isolate, Amycolatopsis sp. MST-108494, was subjected to a panel of fermentation and media optimization trials, supported by analytical chemical profiling, to detect and enhance production of a rare class of secondary metabolites. Chemical fractionation of two complementary fermentations yielded three new polyketides, identified by detailed spectroscopic analysis as the glycosylated macrolactones, amycolatopsins A (1), B (2) and C (3), closely related to the ammocidins and apoptolidins. Amycolatopsins 1 and 3 selectively inhibited growth of Mycobacterium bovis (BCG) and Mycobacterium tuberculosis (H37Rv) when compared with other Gram-positive or Gram-negative bacteria, with 3 exhibiting low levels of cytotoxicity toward mammalian cells. Thus, our data reveal promising structure activity relationship correlations where the antimycobacterial properties of amycolatopsins are enhanced by hydroxylation of the 6-Me (that is, 1 and 3), whereas mammalian cytotoxicity is decreased by hydrolysis of the disaccharide moiety (that is, 3).

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Acknowledgements

We thank AE Lacey (MST) for assistance with the metabolite purification. We acknowledge support from the University of Queensland Institute for Molecular Bioscience and University of Queensland Diamantina Institute. This research was funded in part by The University of Queensland (UQECR1607045).

Author contributions

EL, AC and DV were responsible for the cultivation and isolation of amycolatopsins. ZGK acquired, tabulated and interpreted all spectroscopic data, carried out all bioassays and assembled the Supplementary Information. AAS reviewed all NMR data. AB had oversight of all mycobacterial studies. RJC initiated the research program, and had oversight of all chemical studies and drafting of the manuscript. All authors have given approval to the final version of the manuscript.

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Correspondence to Robert J Capon.

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Supplementary Information accompanies the paper on The Journal of Antibiotics website

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Khalil, Z., Salim, A., Vuong, D. et al. Amycolatopsins A–C: antimycobacterial glycosylated polyketide macrolides from the Australian soil Amycolatopsis sp. MST-108494. J Antibiot 70, 1097–1103 (2017). https://doi.org/10.1038/ja.2017.119

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