TY - JOUR
T1 - Synthesis of macrocyclic nucleoside antibacterials and their interactions with MraY
AU - Nakaya, Takeshi
AU - Yabe, Miyuki
AU - Mashalidis, Ellene H.
AU - Sato, Toyotaka
AU - Yamamoto, Kazuki
AU - Hikiji, Yuta
AU - Katsuyama, Akira
AU - Shinohara, Motoko
AU - Minato, Yusuke
AU - Takahashi, Satoshi
AU - Horiuchi, Motohiro
AU - Yokota, Shin ichi
AU - Lee, Seok Yong
AU - Ichikawa, Satoshi
N1 - Funding Information:
We thank Dr. K. Nishiguchi and Dr. S. Arioka (Shionogi Co., Ltd.) for MraY expression and purification. We thank Dr. Justin Fedor and Ali Hao for critical manuscript reading and help with figures, respectively. This research was supported in part by JSPS KAKENHI Grant-in-Aid for Scientific Research (B) (Grant Number JP16H05097 and JP19H03345 to S.I., JP21H03622 to T.S.), Grant-in Aid for Scientific Research on Innovative Areas “Frontier Research on Chemical Communications” (Nos. JP18H04599 and 20H04757 to S.I.), JSPS KAKENHI Grant-in-Aid for Research for Young Scientist (Grant Number JP19K16648 to T.S.), Takeda Foundation, The Tokyo Biomedical Research Foundation and was partly supported by Hokkaido University, Global Facility Center (GFC), Pharma Science Open Unit (PSOU), funded by MEXT under “Support Program for Implementation of New Equipment Sharing System”, Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under Grant Number JP18am0101093j0002 and JP22ama121039 to S.I. and A.K., AMED under Grant Number JP19ak0101118h0001, AMED under Grant Number 21ak0101118h9903 to T.S., JST START Program: ST211004JO to T.S., Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) from the Ministry of Education, Culture, Sport, Science, and Technology in Japan, and MEXT for the Joint Research Program of the Research Center for Zoonosis Control, Hokkaido University, and National Institute of Health (R01GM120594) to S.-Y.L. This work used NE-CAT beamlines (GM124165), a Pilatus detector (RR029205), an Eiger detector (OD021527) at the APS (DE-AC02-06CH11357).
Funding Information:
We thank Dr. K. Nishiguchi and Dr. S. Arioka (Shionogi Co., Ltd.) for MraY expression and purification. We thank Dr. Justin Fedor and Ali Hao for critical manuscript reading and help with figures, respectively. This research was supported in part by JSPS KAKENHI Grant-in-Aid for Scientific Research (B) (Grant Number JP16H05097 and JP19H03345 to S.I., JP21H03622 to T.S.), Grant-in Aid for Scientific Research on Innovative Areas “Frontier Research on Chemical Communications” (Nos. JP18H04599 and 20H04757 to S.I.), JSPS KAKENHI Grant-in-Aid for Research for Young Scientist (Grant Number JP19K16648 to T.S.), Takeda Foundation, The Tokyo Biomedical Research Foundation and was partly supported by Hokkaido University, Global Facility Center (GFC), Pharma Science Open Unit (PSOU), funded by MEXT under “Support Program for Implementation of New Equipment Sharing System”, Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS)) from AMED under Grant Number JP18am0101093j0002 and JP22ama121039 to S.I. and A.K., AMED under Grant Number JP19ak0101118h0001, AMED under Grant Number 21ak0101118h9903 to T.S., JST START Program: ST211004JO to T.S., Japan Initiative for Global Research Network on Infectious Diseases (J-GRID) from the Ministry of Education, Culture, Sport, Science, and Technology in Japan, and MEXT for the Joint Research Program of the Research Center for Zoonosis Control, Hokkaido University, and National Institute of Health (R01GM120594) to S.-Y.L. This work used NE-CAT beamlines (GM124165), a Pilatus detector (RR029205), an Eiger detector (OD021527) at the APS (DE-AC02-06CH11357).
Publisher Copyright:
© 2022, The Author(s).
PY - 2022/12
Y1 - 2022/12
N2 - The development of new antibacterial drugs with different mechanisms of action is urgently needed to address antimicrobial resistance. MraY is an essential membrane enzyme required for bacterial cell wall synthesis. Sphaerimicins are naturally occurring macrocyclic nucleoside inhibitors of MraY and are considered a promising target in antibacterial discovery. However, developing sphaerimicins as antibacterials has been challenging due to their complex macrocyclic structures. In this study, we construct their characteristic macrocyclic skeleton via two key reactions. Having then determined the structure of a sphaerimicin analogue bound to MraY, we use a structure-guided approach to design simplified sphaerimicin analogues. These analogues retain potency against MraY and exhibit potent antibacterial activity against Gram-positive bacteria, including clinically isolated drug resistant strains of S. aureus and E. faecium. Our study combines synthetic chemistry, structural biology, and microbiology to provide a platform for the development of MraY inhibitors as antibacterials against drug-resistant bacteria.
AB - The development of new antibacterial drugs with different mechanisms of action is urgently needed to address antimicrobial resistance. MraY is an essential membrane enzyme required for bacterial cell wall synthesis. Sphaerimicins are naturally occurring macrocyclic nucleoside inhibitors of MraY and are considered a promising target in antibacterial discovery. However, developing sphaerimicins as antibacterials has been challenging due to their complex macrocyclic structures. In this study, we construct their characteristic macrocyclic skeleton via two key reactions. Having then determined the structure of a sphaerimicin analogue bound to MraY, we use a structure-guided approach to design simplified sphaerimicin analogues. These analogues retain potency against MraY and exhibit potent antibacterial activity against Gram-positive bacteria, including clinically isolated drug resistant strains of S. aureus and E. faecium. Our study combines synthetic chemistry, structural biology, and microbiology to provide a platform for the development of MraY inhibitors as antibacterials against drug-resistant bacteria.
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U2 - 10.1038/s41467-022-35227-z
DO - 10.1038/s41467-022-35227-z
M3 - Article
C2 - 36539416
AN - SCOPUS:85144247611
VL - 13
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 7575
ER -