Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37- N¹)-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism

TY - JOUR

T1 - Thienopyrimidinone Derivatives That Inhibit Bacterial tRNA (Guanine37- N1)-Methyltransferase (TrmD) by Restructuring the Active Site with a Tyrosine-Flipping Mechanism

AU - Zhong, Wenhe

AU - Pasunooti, Kalyan Kumar

AU - Balamkundu, Seetharamsing

AU - Wong, Yee Hwa

AU - Nah, Qianhui

AU - Gadi, Vinod

AU - Gnanakalai, Shanmugavel

AU - Chionh, Yok Hian

AU - McBee, Megan E.

AU - Gopal, Pooja

AU - Lim, Siau Hoi

AU - Olivier, Nelson

AU - Buurman, Ed T.

AU - Dick, Thomas

AU - Liu, Chuan Fa

AU - Lescar, Julien

AU - Dedon, Peter C.

N1 - Publisher Copyright: © 2019 American Chemical Society.

PY - 2019/9/12

Y1 - 2019/9/12

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/85072103389

U2 - 10.1021/acs.jmedchem.9b00582

DO - 10.1021/acs.jmedchem.9b00582

M3 - Article

C2 - 31442049

SN - 0022-2623

VL - 62

SP - 7788

EP - 7805

JO - Journal of medicinal chemistry

JF - Journal of medicinal chemistry

IS - 17

ER -