1380109-75-0Relevant academic research and scientific papers
Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37- N1)-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism
Zhong, Wenhe,Pasunooti, Kalyan Kumar,Balamkundu, Seetharamsing,Wong, Yee Hwa,Nah, Qianhui,Gadi, Vinod,Gnanakalai, Shanmugavel,Chionh, Yok Hian,McBee, Megan E.,Gopal, Pooja,Lim, Siau Hoi,Olivier, Nelson,Buurman, Ed T.,Dick, Thomas,Liu, Chuan Fa,Lescar, Julien,Dedon, Peter C.
supporting information, p. 7788 - 7805 (2019/10/11)
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.
Pyridone-conjugated monobactam antibiotics with gram-negative activity
Brown, Matthew F.,Mitton-Fry, Mark J.,Arcari, Joel T.,Barham, Rose,Casavant, Jeffrey,Gerstenberger, Brian S.,Han, Seungil,Hardink, Joel R.,Harris, Thomas M.,Hoang, Thuy,Huband, Michael D.,Lall, Manjinder S.,Lemmon, M. Megan,Li, Chao,Lin, Jian,McCurdy, Sandra P.,McElroy, Eric,McPherson, Craig,Marr, Eric S.,Mueller, John P.,Mullins, Lisa,Nikitenko, Antonia A.,Noe, Mark C.,Penzien, Joseph,Plummer, Mark S.,Schuff, Brandon P.,Shanmugasundaram, Veerabahu,Starr, Jeremy T.,Sun, Jianmin,Tomaras, Andrew,Young, Jennifer A.,Zaniewski, Richard P.
, p. 5541 - 5552 (2013/07/26)
Herein we describe the structure-aided design and synthesis of a series of pyridone-conjugated monobactam analogues with in vitro antibacterial activity against clinically relevant Gram-negative species including Pseudomonas aeruginosa, Klebsiella pneumoniae, and Escherichia coli. Rat pharmacokinetic studies with compound 17 demonstrate low clearance and low plasma protein binding. In addition, evidence is provided for a number of analogues suggesting that the siderophore receptors PiuA and PirA play a role in drug uptake in P. aeruginosa strain PAO1.
MONOBACTAMS
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, (2012/06/16)
The present invention is directed to a new class of monobactam derivatives and their use for treating bacterial infections.
