dc.contributor.author | Zhong, Wenhe | |
dc.contributor.author | Pasunooti, Kalyan Kumar | |
dc.contributor.author | Balamkundu, Seetharamsing | |
dc.contributor.author | Wong, Yee Hwa | |
dc.contributor.author | Nah, Qianhui | |
dc.contributor.author | Gadi, Vinod | |
dc.contributor.author | Gnanakalai, Shanmugavel | |
dc.contributor.author | Chionh, Yok Hian | |
dc.contributor.author | McBee, Megan E. | |
dc.contributor.author | Gopal, Pooja | |
dc.contributor.author | Lim, Siau Hoi | |
dc.contributor.author | Olivier, Nelson | |
dc.contributor.author | Buurman, Ed T. | |
dc.contributor.author | Dick, Thomas | |
dc.contributor.author | Liu, Chuan Fa | |
dc.contributor.author | Lescar, Julien | |
dc.contributor.author | Dedon, Peter C | |
dc.date.accessioned | 2019-09-23T17:34:10Z | |
dc.date.available | 2019-09-23T17:34:10Z | |
dc.date.issued | 2019-08 | |
dc.date.submitted | 2019-04 | |
dc.identifier.issn | 0022-2623 | |
dc.identifier.issn | 1520-4804 | |
dc.identifier.uri | https://hdl.handle.net/1721.1/122276 | |
dc.description.abstract | Among the >120 modified ribonucleosides in the prokaryotic epitranscriptome, many tRNA modifications are critical to bacterial survival, which makes their synthetic enzymes ideal targets for antibiotic development. Here we performed a structure-based design of inhibitors of tRNA-(N1G37) methyltransferase, TrmD, which is an essential enzyme in many bacterial pathogens. On the basis of crystal structures of TrmDs from Pseudomonas aeruginosa and Mycobacterium tuberculosis, we synthesized a series of thienopyrimidinone derivatives with nanomolar potency against TrmD in vitro and discovered a novel active site conformational change triggered by inhibitor binding. This tyrosine-flipping mechanism is uniquely found in P. aeruginosa TrmD and renders the enzyme inaccessible to the cofactor S-adenosyl-l-methionine (SAM) and probably to the substrate tRNA. Biophysical and biochemical structure-activity relationship studies provided insights into the mechanisms underlying the potency of thienopyrimidinones as TrmD inhibitors, with several derivatives found to be active against Gram-positive and mycobacterial pathogens. These results lay a foundation for further development of TrmD inhibitors as antimicrobial agents. | en_US |
dc.language.iso | en | |
dc.publisher | American Chemical Society (ACS) | en_US |
dc.relation.isversionof | http://dx.doi.org/10.1021/acs.jmedchem.9b00582 | en_US |
dc.rights | Creative Commons Attribution-NonCommercial-NoDerivs License | en_US |
dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | en_US |
dc.source | ACS | en_US |
dc.title | Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37-N¹)-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism | en_US |
dc.type | Article | en_US |
dc.identifier.citation | Zhong, Wenhe et al. "Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37-N¹)-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism." Journal of Medicinal Chemistry 62, 17 (August 2019): 7788-7805 © 2019 American Chemical Society | en_US |
dc.contributor.department | Massachusetts Institute of Technology. Department of Biological Engineering | en_US |
dc.relation.journal | Journal of Medicinal Chemistry | en_US |
dc.eprint.version | Final published version | en_US |
dc.type.uri | http://purl.org/eprint/type/JournalArticle | en_US |
eprint.status | http://purl.org/eprint/status/PeerReviewed | en_US |
dc.date.updated | 2019-09-20T14:42:47Z | |
dspace.date.submission | 2019-09-20T14:42:51Z | |
mit.journal.volume | 62 | en_US |
mit.journal.issue | 17 | en_US |