論文 - 詳細
| RRC ID | 84524 |
|---|---|
| 著者 | Hayashi H, Saijo E, Hirata K, Murakami S, Okuda H, Kodama EN, Hasegawa K, Murayama K. |
| タイトル | SHIN-2 exerts potent activity against VanA-type vancomycin-resistant Enterococcus faecium in vitro by stabilizing the active site loop of serine hydroxymethyltransferase. |
| ジャーナル | Arch Biochem Biophys |
| 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. |
| 巻・号 | 761 |
| ページ | 110160 |
| 公開日 | 2024-11-1 |
| DOI | 10.1016/j.abb.2024.110160 |
| PII | S0003-9861(24)00282-0 |
| PMID | 39313141 |
| MeSH | Anti-Bacterial Agents* / chemistry Anti-Bacterial Agents* / pharmacology Bacterial Proteins / antagonists & inhibitors Bacterial Proteins / chemistry Bacterial Proteins / genetics Bacterial Proteins / metabolism Catalytic Domain* Enterococcus faecium* / enzymology Glycine Hydroxymethyltransferase* / antagonists & inhibitors Glycine Hydroxymethyltransferase* / chemistry Glycine Hydroxymethyltransferase* / genetics Glycine Hydroxymethyltransferase* / metabolism Humans Vancomycin / chemistry Vancomycin / pharmacology Vancomycin Resistance / genetics Vancomycin-Resistant Enterococci / enzymology |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 各媒体での言及数の合計 | 0 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| 一般微生物 | JCM5804 JCM7783 |