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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Price, N., Hartman, T., Li, J. et al. Modified tunicamycins with reduced eukaryotic toxicity that enhance the antibacterial activity of β-lactams. J Antibiot 70, 1070–1077 (2017). https://doi.org/10.1038/ja.2017.101
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DOI: https://doi.org/10.1038/ja.2017.101
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