Original Article | Published:

Modified tunicamycins with reduced eukaryotic toxicity that enhance the antibacterial activity of β-lactams

The Journal of Antibiotics volume 70, pages 10701077 (2017) | Download Citation

Abstract

Tunicamycins (TUN) are inhibitors of the UDP-HexNAc: polyprenol-P HexNAc-1-P transferase family of enzymes, which initiate the biosynthesis of bacterial peptidoglycan and catalyze the first step in eukaryotic protein N-glycosylation. The TUN are therefore general and potent toxins to both eukaryotes and prokaryotes. Screening a library of synthetic TUN against Bacillus and yeast identified TUN that are antibacterial, but have significantly reduced eukaryotic toxicity. One of these (Tun-15:0) differs from the native TUN control only by the lack of the conjugated double bond in the tunicaminyl N-acyl group. Tun-15:0 also showed reduced inhibition for protein N-glycosylation in a Pichia-based bioassay. Natural TUN was subsequently modified by chemically reducing the N-acyl double bond (TunR1) or both the N-acyl and uridyl double bonds (TunR2). TunR1 and TunR2 retain their antibacterial activity, but with considerably reduced eukaryotic toxicity. In protein N-glycosylation bioassays, TunR1 is a less potent inhibitor than native TUN and TunR2 is entirely inactive. Importantly, the less toxic TunR1 and TunR2 both enhance the antibacterial activity of β-lactams: oxacillin by 32- to 64-fold, comparable with native TUN, and with similar enhancements for methicillin and penicillin G. Hence, the modified TUNs, TunR1 and TunR2, are potentially important as less-toxic synergistic enhancers of the β-lactams.

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Acknowledgements

BY acknowledges the support of the National Natural Science Foundation of China (21372253 and 21432012). We thank WW Metcalf (University of Illinois, Champaign, IL, USA) and JO Rich (ARS-USDA, Peoria, IL, USA) for the initially review of the manuscript. A provisional patent application (patent number 62/450,760) has been filed. Mention of any trade names or commercial products is solely for the purpose of providing specific information and does not imply recommendation or endorsement by the US Department of Agriculture. USDA is an equal opportunity provider and employer.

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Affiliations

  1. Agricultural Research Service, US Department of Agriculture, National Center for Agricultural Utilization Research, Peoria, IL, USA

    • Neil PJ Price
    • , Trina M Hartman
    • , Todd A Naumann
    •  & Kenneth M Bischoff
  2. State Key Laboratory of Bioorganic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai, China

    • Jiakun Li
    •  & Biao Yu
  3. Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, IL, USA

    • Kiran K Velpula
    •  & Maheedhara R Guda

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The authors declare no conflict of interest.

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Correspondence to Neil PJ Price.

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DOI

https://doi.org/10.1038/ja.2017.101

Supplementary Information accompanies the paper on The Journal of Antibiotics website (http://www.nature.com/ja)