The Berkeleylactones, Antibiotic Macrolides from Fungal Coculture

Andrea A. Stierle; Donald B. Stierle; Daniel Decato; Nigel D. Priestley; Jeremy B. Alverson; John Hoody; Kelly McGrath; Dorota Klepacki

doi:10.1021/acs.jnatprod.7b00133

The Berkeleylactones, Antibiotic Macrolides from Fungal Coculture

Andrea A. Stierle
, Donald B. Stierle
, Daniel Decato
, Nigel D. Priestley
, Jeremy B. Alverson
, John Hoody
, Kelly McGrath
, Dorota Klepacki

Research output: Contribution to journal › Article › peer-review

104 Scopus citations

Abstract

A carefully timed coculture fermentation of Penicillium fuscum and P. camembertii/clavigerum yielded eight new 16-membered-ring macrolides, berkeleylactones A-H (1, 4, 6-9, 12, 13), as well as the known antibiotic macrolide A26771B (5), patulin, and citrinin. There was no evidence of the production of the berkeleylactones or A26771B (5) by either fungus when grown as axenic cultures. The structures were deduced from analyses of spectral data, and the absolute configurations of compounds 1 and 9 were determined by single-crystal X-ray crystallography. Berkeleylactone A (1) exhibited the most potent antimicrobial activity of the macrolide series, with low micromolar activity (MIC = 1-2 μg/mL) against four MRSA strains, as well as Bacillus anthracis, Streptococcus pyogenes, Candida albicans, and Candida glabrata. Mode of action studies have shown that, unlike other macrolide antibiotics, berkeleylactone A (1) does not inhibit protein synthesis nor target the ribosome, which suggests a novel mode of action for its antibiotic activity.

Original language	English
Pages (from-to)	1150-1160
Number of pages	11
Journal	Journal of Natural Products
Volume	80
Issue number	4
DOIs	https://doi.org/10.1021/acs.jnatprod.7b00133
State	Published - Apr 28 2017

Funding

We thank Prof. A. Mankin (Center for Biomolecular Sciences, College of Pharmacy, University of Illinois at Chicago) for testing berkleylactone A (1) in the cell-free translation and extension inhibition assays. We thank NSF grant no. CHE- 9977213 for acquisition of an NMR spectrometer and the M.J. Murdock Charitable Trust ref no. 99009 (J.V.Z.; 11/18/99) for acquisition of the mass spectrometer. The project described was supported by NIH grants P20GM103546 and 5P30NS055022. The Macromolecular X-ray Diffraction Core Facility at the University of Montana was supported by a Centers of Biomedical Research Excellence grant from the National Institute of General Medical Sciences (P20GM103546) and by the National Science Foundation (NSF)-MRI (CHE-1337908). Antibiotic data for linezolid, vancomycin, erythromycin, clindamycin, levofloxacin, doxycycline, and cefazolin were provided by Hartford Hospital Center for Anti-Infective Research and Development (CAIRD). We also thank Hartford Hospital for the methicillin-resistant strains of Staphylococcus aureus used in this study

Funders	Funder number
Saint Francis Hospital and Medical Center Hartford
5P30NS055022
P20GM103546
CHE-1337908

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10.1021/acs.jnatprod.7b00133

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title = "The Berkeleylactones, Antibiotic Macrolides from Fungal Coculture",

abstract = "A carefully timed coculture fermentation of Penicillium fuscum and P. camembertii/clavigerum yielded eight new 16-membered-ring macrolides, berkeleylactones A-H (1, 4, 6-9, 12, 13), as well as the known antibiotic macrolide A26771B (5), patulin, and citrinin. There was no evidence of the production of the berkeleylactones or A26771B (5) by either fungus when grown as axenic cultures. The structures were deduced from analyses of spectral data, and the absolute configurations of compounds 1 and 9 were determined by single-crystal X-ray crystallography. Berkeleylactone A (1) exhibited the most potent antimicrobial activity of the macrolide series, with low micromolar activity (MIC = 1-2 μg/mL) against four MRSA strains, as well as Bacillus anthracis, Streptococcus pyogenes, Candida albicans, and Candida glabrata. Mode of action studies have shown that, unlike other macrolide antibiotics, berkeleylactone A (1) does not inhibit protein synthesis nor target the ribosome, which suggests a novel mode of action for its antibiotic activity.",

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The Berkeleylactones, Antibiotic Macrolides from Fungal Coculture

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