Discovery and evaluation of new compounds targeting ribosomal protein S1 in antibiotic-resistant Mycobacterium Tuberculosis
Copyright © 2020 Elsevier Masson SAS. All rights reserved..
The emergence of antibiotic-resistant Mycobacterium Tuberculosis (Mtb) infections compels new treatment strategies, of which targeting trans-translation is promising. During the trans-translation process, the ribosomal protein S1 (RpsA) plays a key role, and the Ala438 mutant is related to pyrazinamide (PZA) resistance, which shows its effects after being hydrolysed to pyrazinoic acid (POA). In this study, based on the structure of the RpsA C-terminal domain (RpsA-CTD) and POA complex, new compounds were designed. After being synthesized, the compounds were tested in vitro with saturation transfer difference (STD), fluorescence quenching titration (FQT) and chemical shift perturbation (CSP) experiments. Finally, six of the 17 new compounds have high affinity for both RpsA-CTD and its Ala438 deletion mutant. The active compounds provide new choices for targeting trans-translation in Mtb, and the analysis of the structure-activity relationships will be helpful for further structural modifications based on derivatives of 2-((hypoxanthine-2-yl)thio)acetic acid and 2-((5-hydroxylflavone-7-yl)oxy)acetamide.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2020 |
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| Erschienen: |
2020 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:196 |
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| Enthalten in: |
European journal of medicinal chemistry - 196(2020) vom: 15. Juni, Seite 112317 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Dai, Yazhuang [VerfasserIn] |
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| Links: |
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| Themen: |
2TN51YD919 |
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| Anmerkungen: |
Date Completed 29.12.2020 Date Revised 29.12.2020 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.ejmech.2020.112317 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM308960904 |
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| 245 | 1 | 0 | |a Discovery and evaluation of new compounds targeting ribosomal protein S1 in antibiotic-resistant Mycobacterium Tuberculosis |
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| 500 | |a Date Revised 29.12.2020 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2020 Elsevier Masson SAS. All rights reserved. | ||
| 520 | |a The emergence of antibiotic-resistant Mycobacterium Tuberculosis (Mtb) infections compels new treatment strategies, of which targeting trans-translation is promising. During the trans-translation process, the ribosomal protein S1 (RpsA) plays a key role, and the Ala438 mutant is related to pyrazinamide (PZA) resistance, which shows its effects after being hydrolysed to pyrazinoic acid (POA). In this study, based on the structure of the RpsA C-terminal domain (RpsA-CTD) and POA complex, new compounds were designed. After being synthesized, the compounds were tested in vitro with saturation transfer difference (STD), fluorescence quenching titration (FQT) and chemical shift perturbation (CSP) experiments. Finally, six of the 17 new compounds have high affinity for both RpsA-CTD and its Ala438 deletion mutant. The active compounds provide new choices for targeting trans-translation in Mtb, and the analysis of the structure-activity relationships will be helpful for further structural modifications based on derivatives of 2-((hypoxanthine-2-yl)thio)acetic acid and 2-((5-hydroxylflavone-7-yl)oxy)acetamide | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Anti-Tuberculosis agents | |
| 650 | 4 | |a Pyrazinamide | |
| 650 | 4 | |a Ribosomal protein S1 | |
| 650 | 4 | |a Trans-translation | |
| 650 | 7 | |a Acetamides |2 NLM | |
| 650 | 7 | |a Anti-Bacterial Agents |2 NLM | |
| 650 | 7 | |a Ribosomal Proteins |2 NLM | |
| 650 | 7 | |a ribosomal protein S1 |2 NLM | |
| 650 | 7 | |a Hypoxanthine |2 NLM | |
| 650 | 7 | |a 2TN51YD919 |2 NLM | |
| 650 | 7 | |a acetamide |2 NLM | |
| 650 | 7 | |a 8XOE1JSO29 |2 NLM | |
| 700 | 1 | |a Xu, Yinqiu |e verfasserin |4 aut | |
| 700 | 1 | |a Guo, Chenyun |e verfasserin |4 aut | |
| 700 | 1 | |a Xue, Xiaowen |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Donghai |e verfasserin |4 aut | |
| 700 | 1 | |a Lin, Kejiang |e verfasserin |4 aut | |
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