Serine hydroxymethyltransferase as a potential target of antibacterial agents acting synergistically with one-carbon metabolism-related inhibitors
Yuko Makino, Chihiro Oe, Kazuya Iwama, Satoshi Suzuki, Akie Nishiyama, Kazuya Hasegawa, Haruka Okuda, Kazushige Hirata, Mariko Ueno, Kumi Kawaji, Mina Sasano, Emiko Usui, Toshiaki Hosaka, Yukako Yabuki, Mikako Shirouzu, Makoto Katsumi, Kazutaka Murayama, Hironori Hayashi, Eiichi Kodama
Abstract
Abstract Serine hydroxymethyltransferase (SHMT) produces 5,10-methylenetetrahydrofolate (CH 2 -THF) from tetrahydrofolate with serine to glycine conversion. SHMT is a potential drug target in parasites, viruses and cancer. (+)-SHIN-1 was developed as a human SHMT inhibitor for cancer therapy. However, the potential of SHMT as an antibacterial target is unknown. Here, we show that (+)-SHIN-1 bacteriostatically inhibits the growth of Enterococcus faecium at a 50% effective concentration of 10 –11 M and synergistically enhances the antibacterial activities of several nucleoside analogues. Our results, including crystal structure analysis, indicate that (+)-SHIN-1 binds tightly to E. faecium SHMT ( efm SHMT). Two variable loops in SHMT are crucial for inhibitor binding, and serine binding to efm SHMT enhances the affinity of (+)-SHIN-1 by stabilising the loop structure of efm SHMT. The findings highlight the potency of SHMT as an antibacterial target and the possibility of developing SHMT inhibitors for treating bacterial, viral and parasitic infections and cancer.