2. Academic Validation
  3. SHIN-2 exerts potent activity against VanA-type vancomycin-resistant Enterococcus faecium in vitro by stabilizing the active site loop of serine hydroxymethyltransferase

SHIN-2 exerts potent activity against VanA-type vancomycin-resistant Enterococcus faecium in vitro by stabilizing the active site loop of serine hydroxymethyltransferase

  • Arch Biochem Biophys. 2024 Nov:761:110160. doi: 10.1016/j.abb.2024.110160.
Hironori Hayashi 1,  Erika Saijo 2,  Kazushige Hirata 3,  Shumei Murakami 4,  Haruka Okuda 4,  Eiichi N Kodama 5,  Kazuya Hasegawa 6,  Kazutaka Murayama 7
Affiliations

Affiliations

  • 1 Division of Infectious Diseases, International Research Institute of Disaster Science, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan. Electronic address: hironori.hayashi.b1@tohoku.ac.jp.
  • 2 Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan.
  • 3 Department of Clinical Laboratory Medicine, Tohoku University Hospital, 1-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8574, Japan.
  • 4 Division of Infectious Diseases, International Research Institute of Disaster Science, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
  • 5 Division of Infectious Diseases, International Research Institute of Disaster Science, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan; Department of Infectious Diseases, Tohoku University Graduate School of Medicine, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan; Tohoku Medical Megabank Organization, Tohoku University, 2-1, Seiryo-machi, Aoba-ku, Sendai, Miyagi, 980-8575, Japan.
  • 6 Structural Biology Division, Japan Synchrotron Radiation Research Institute, 1-1-1 Kouto, Sayo, Sayo, Hyogo, Japan.
  • 7 Division of Biomedical Measurements and Diagnostics, Graduate School of Biomedical Engineering, Tohoku University, Sendai, Japan. Electronic address: kazutaka.murayama.d4@tohoku.ac.jp.
PMID: 39313141 DOI: 10.1016/j.abb.2024.110160
Abstract

Novel classes of Antibiotics are needed to improve the resilience of the healthcare system to antimicrobial resistance (AMR), including vancomycin resistance. vanA gene cluster is a cause of vancomycin resistance. This gene cluster is transferred and spreads vancomycin resistance from Enterococcus spp. to Staphylococcus aureus. Therefore, novel Antibacterial agents are required to combat AMR, including vanA-type vancomycin resistance. Serine hydroxymethyltransferase (SHMT) is a key target of Antibacterial agents. However, the specific binding mechanisms of SHMT inhibitors remain unclear. Detailed structural information will contribute to understanding these mechanisms. In this study, we found that (+)-SHIN-2, the first in vivo active inhibitor of human SHMT, is strongly bound to the Enterococcus faecium SHMT (efmSHMT). Comparison of the crystal structures of apo- and (+)-SHIN-2-boud efmSHMT revealed that (+)-SHIN-2 stabilized the active site loop of efmSHMT via hydrogen bonds, which are critical for efmSHMT inhibition. Additionally, (+)-SHIN-2 formed hydrogen bonds with serine, forming the Schiff's base with pyridoxal 5'-phosphate, which is a co-factor of SHMT. Furthermore, (+)-SHIN-2 exerted biostatic effects on vancomycin-susceptible and vanA-type vancomycin-resistant E. faecium in vitro, indicating that SHMT inhibitors do not induce cross-resistance to vanA-type vancomycin. Overall, these findings can aid in the design of novel SHMT inhibitors to combat AMR, including vancomycin resistance.

Keywords

Antibacterial resistance; Drug development; Infectious disease; One carbon metabolism; SHMT inhibitor.

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