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ARS Home » Midwest Area » Peoria, Illinois » National Center for Agricultural Utilization Research » Renewable Product Technology Research » Research » Publications at this Location » Publication #360118

Research Project: Technologies for Producing Renewable Bioproducts

Location: Renewable Product Technology Research

Title: Exploring the active site of the antibacterial target MraY by modified tunicamycins

item HERING, JENNY - Astrazeneca Research & Development
item DUNEVALL, ELIN - University Of Gothenburg
item SNIJDER, ARJAN - Astrazeneca Research & Development
item ERIKSSON, PER-OLOF - Astrazeneca Research & Development
item Jackson, Michael - Mike
item Hartman, Trina
item TING, RAN - Guangdong Institute Of Applied Biological Resources
item CHEN, HONGMING - Guangdong Institute Of Applied Biological Resources
item Price, Neil
item BRANDEN, GISELA - University Of Gothenburg
item EK, MARGARETA - University Of Gothenburg

Submitted to: ACS Chemical Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 10/26/2020
Publication Date: 11/9/2020
Citation: Hering, J., Dunevall, E., Snijder, A., Eriksson, P., Jackson, M.A., Hartman, T.M., Ting, R., Chen, H., Price, N.P., Branden, G., Ek, M. 2020. Exploring the active site of the antibacterial target MraY by modified tunicamycins. ACS Chemical Biology. 15(11):2885-2895.

Interpretive Summary: Antibiotic resistance is a major threat to medicine and agriculture. Tunicamycins (TUNs) are a group of antibiotics produced by soil bacterium that can potentially be used to combat this resistance. There are several natural TUNs that differ by the length and branching of an attached fatty acid chain. In this work, we have purified these different TUNs. We next assayed the effects of these different TUNS on MraY, an enzyme needed for bacteria to grow. Some TUNs more effectively block the function of bacterial MraY and may be more valuable as potent antibiotics. We also tested modified TUNs and found some that are less active against the version of MraY found in animals, which may result in less toxicity associated with therapeutic use. Some of these modified TUNs may find uses as new antibiotics for agricultural and health purposes.

Technical Abstract: The alarming growth of antibiotic resistance that is currently ongoing is a serious threat to human health. One of the most promising novel antibiotic targets is MraY (phospho-MurNAc-pentapeptide-transferase), an essential enzyme in bacterial cell wall synthesis. Through recent advances in biochemical research, there is now structural information available for MraY, and for its human homologue GPT (GlcNAc-1-P-transferase), that opens up exciting possibilities for structure-based drug design. The antibiotic compound tunicamycin is a natural product inhibitor of MraY that is also toxic to eukaryotes through its binding to GPT. In this work, we have used tunicamycin and modified versions of tunicamycin as tool compounds to explore the active site of MraY and to gain further insight into what determines inhibitor potency. We have investigated tunicamycin variants where the following motifs have been modified: the length and branching of the tunicamycin fatty acyl chain, the saturation of the fatty acyl chain, the 6'-hydroxyl group of the GlcNAc ring, and the ring structure of the uracil motif. The compounds are analyzed in terms of how potently they bind to MraY, inhibit the activity of the enzyme, and affect the protein thermal stability. Finally, we rationalize these results in the context of the protein structures of MraY and GPT.