Abstract
The β-lactams are the most widely used group of antibiotics in human health and agriculture, but this is under threat due to the persistent rise of pathogenic resistance. Several compounds, including tunicamycin (TUN), can enhance the antibacterial activity of the β-lactams to the extent of overcoming resistance, but the mammalian toxicity of TUN has precluded its use in this role. Selective hydrogenation of TUN produces modified compounds (TunR1 and TunR2), which retain the enhancement of β-lactams while having much lower mammalian toxicity. Here we show that TunR1 and TunR2 enhance the antibacterial activity of multiple β-lactam family members, including penems, cephems, and third-generation penicillins, to a similar extent as does the native TUN. Eleven of the β-lactams tested were enhanced from 2 to >256-fold against Bacillus subtilis, with comparable results against a penicillin G-resistant strain. The most significant enhancements were obtained with third-generation aminothiazolidyl cephems, including cefotaxime, ceftazidime, and cefquinome. These results support the potential of low toxicity tunicamycin analogs (TunR1 and TunR2) as clinically valid, synergistic enhancers for a broad group of β-lactam antibiotics.
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Acknowledgements
We thank David Lee for technical assistance and Dr Christopher Skory for pre-review of the manuscript. VS acknowledges the South African Medical Research Council (SAMRC) for funding. 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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NPJP, MAJ, PFD and VS designed research; NPJP, MAJ, VS, PFD, TMH and JAB performed research; NPJP, MAJ, and VS analyzed the data; and NPJP, MAJ, VS, PFD and TMH wrote the paper.
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Price, N.P.J., Jackson, M.A., Singh, V. et al. Synergistic enhancement of beta-lactam antibiotics by modified tunicamycin analogs TunR1 and TunR2. J Antibiot 72, 807–815 (2019). https://doi.org/10.1038/s41429-019-0220-x
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DOI: https://doi.org/10.1038/s41429-019-0220-x
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