Serine hydroxymethyltransferase as a potential target of antibacterial agents acting synergistically with one-carbon metabolism-related inhibitors

• DOI: 10.1038/s42003-022-03555-x
• Publication Date: 2022-06-23T16:35:56Z
• Authors: 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 N. Kodama
• Keywords: Glycine Hydroxymethyltransferase; 0303 health sciences; 03 medical and health sciences; QH301-705.5; Neoplasms; Serine; Humans; Biology (General); Article; Carbon; Anti-Bacterial Agents; 3. Good health

AbstractSerine hydroxymethyltransferase (SHMT) produces 5,10-methylenetetrahydrofolate (CH2-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 (efmSHMT). Two variable loops in SHMT are crucial for inhibitor binding, and serine binding to efmSHMT enhances the affinity of (+)-SHIN-1 by stabilising the loop structure of efmSHMT. 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.