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Mode of Action and Heterologous Expression of the Natural Product Antibiotic Vancoresmycin

Lookup NU author(s): Dr Bernhard Kepplinger, Stephanie Morton, Dr Kenneth Seistrup, Dr Adam Hopkins, Dr Henrik Strahl von Schulten, Dr Michael Hall, Professor Jeff Errington, Dr Nicholas Allenby

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This is the authors' accepted manuscript of an article that has been published in its final definitive form by American Chemical Society , 2018.

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Abstract

Antibiotics that interfere with the bacterial cytoplasmic membrane have long term potential for the treatment of infectious diseases, as this mode of action is anticipated to result in low resistance frequency. Vancoresmycin is an understudied natural product antibiotic consisting of a terminal tetramic acid moiety fused to a linear, highly oxygenated, stereochemically complex polyketide chain. Vancoresmycin shows minimum inhibitory concentrations (MIC) from 0.125 to 2 µg/mL against a range of clinically relevant, antibiotic-resistant Gram-positive bacteria. Through a comprehensive mode-of-action study, utilising Bacillus subtilis reporter strains, DiSC3(5) depolarization assays and fluorescence microscopy, we have shown that vancoresmycin selectively targets the cytoplasmic membrane of Gram-positive bacteria via a non-pore forming, concentration-dependent depolarization mechanism. Whole genome sequencing of the producing strain allowed identification of the 141 kbp gene cluster encoding for vancoresmycin biosynthesis and a preliminary model for its biosynthesis. The size and complex structure of vancoresmycin could confound attempts to generate synthetic analogues. To overcome this problem and facilitate future studies, we identified, cloned and expressed the 141 kbp biosynthetic gene cluster in Streptomyces coelicolor M1152.Elucidation of the mode-of-action of vancoresmycin, together with the heterologous expression system will greatly facilitate further studies of this and related molecules.


Publication metadata

Author(s): Kepplinger B, Morton S, Seistrup K, Marrs E, Hopkins A, Perry J, Strahl H, Hall M, Errington J, Allenby N

Publication type: Article

Publication status: Published

Journal: ACS Chemical Biology

Year: 2018

Volume: 13

Issue: 1

Pages: 207-214

Print publication date: 19/01/2018

Online publication date: 29/11/2017

Acceptance date: 30/11/2017

Date deposited: 01/12/2017

ISSN (print): 1554-8929

ISSN (electronic): 1554-8937

Publisher: American Chemical Society

URL: https://doi.org/10.1021/acschembio.7b00733

DOI: 10.1021/acschembio.7b00733


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