Identification of actinomycin D as a specific inhibitor of the alternative pathway of peptidoglycan biosynthesis

Abstract

Peptidoglycan is an indispensable component of bacterial cell walls. We recently discovered an alternative peptidoglycan biosynthetic pathway, which involves two enzymes, MurD2 and MurL, catalyzing the ligation of l-Glu to UDP-MurNAc-l-Ala and epimerization of the terminal l-Glu of the MurD2 product, respectively. Because the pathway operates in Xanthomonas oryze, a pathogen causing bacterial blight of rice, we searched for specific inhibitors from metabolites produced by actinomycetes to obtain a lead compound to function as an agrochemical. Actinomycin D was isolated from Streptomyces parvulus NBRC 13193 as a specific inhibitor of the pathway. In vitro analysis indicated that actinomycin D inhibited the MurD2 reaction.

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Acknowledgements

This study was supported in part by Grants-in-Aid for Research on Innovative Areas from MEXT, Japan (JSPS KAKENHI Grant Number 16H06452 to T.D.), Grants-in-Aid for Scientific Research from JSPS (18H03937 to T.D. and 18K05449 to Y.O.) and the Uehara Memorial Foundation to T.D. The authors thank Mr. Masafumi Nakao for the assistance in the preparation of UDP-MurNAc-L-Ala. The authors also thank Dr. Eri Fukushi at the GC-MS and NMR Laboratory, Graduate School of Agriculture, Hokkaido University, for acquiring the NMR spectra. We thank Kate Fox, DPhil, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript.

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Correspondence to Yasushi Ogasawara or Tohru Dairi.

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Ogasawara, Y., Shimizu, Y., Sato, Y. et al. Identification of actinomycin D as a specific inhibitor of the alternative pathway of peptidoglycan biosynthesis. J Antibiot 73, 125–127 (2020). https://doi.org/10.1038/s41429-019-0252-2

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