Indole Propionic Acid Disturbs the Normal Function of Tryptophanyl-tRNA Synthetase in Mycobacterium tuberculosis
Tuberculosis (TB) is the leading infectious disease caused by Mycobacterium tuberculosis and the second-most contagious killer after COVID-19. The emergence of drug-resistant TB has caused a great need to identify and develop new anti-TB drugs with novel targets. Indole propionic acid (IPA), a structural analog of tryptophan (Trp), is active against M. tuberculosis in vitro and in vivo. It has been verified that IPA exerts its antimicrobial effect by mimicking Trp as an allosteric inhibitor of TrpE, which is the first enzyme in the Trp synthesis pathway of M. tuberculosis. However, other Trp structural analogs, such as indolmycin, also target tryptophanyl-tRNA synthetase (TrpRS), which has two functions in bacteria: synthesis of tryptophanyl-AMP by catalyzing ATP + Trp and producing Trp-tRNATrp by transferring Trp to tRNATrp. So, we speculate that IPA may also target TrpRS. In this study, we found that IPA can dock into the Trp binding pocket of M. tuberculosis TrpRS (TrpRSMtb), which was further confirmed by isothermal titration calorimetry (ITC) assay. The biochemical analysis proved that TrpRS can catalyze the reaction between IPA and ATP to generate pyrophosphate (PPi) without Trp as a substrate. Overexpression of wild-type trpS in M. tuberculosis increased the MIC of IPA to 32-fold, and knock-down trpS in Mycolicibacterium smegmatis made it more sensitive to IPA. The supplementation of Trp in the medium abrogated the inhibition of M. tuberculosis by IPA. We demonstrated that IPA can interfere with the function of TrpRS by mimicking Trp, thereby impeding protein synthesis and exerting its anti-TB effect.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
|---|---|
| Enthalten in: |
ACS infectious diseases - 10(2024), 4 vom: 12. Apr., Seite 1201-1211 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Han, Xingli [VerfasserIn] |
|---|
| Links: |
|---|
| Anmerkungen: |
Date Completed 15.04.2024 Date Revised 15.04.2024 published: Print-Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1021/acsinfecdis.3c00585 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM369473922 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM369473922 | ||
| 003 | DE-627 | ||
| 005 | 20240415233344.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240309s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1021/acsinfecdis.3c00585 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1376.xml |
| 035 | |a (DE-627)NLM369473922 | ||
| 035 | |a (NLM)38457660 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Han, Xingli |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Indole Propionic Acid Disturbs the Normal Function of Tryptophanyl-tRNA Synthetase in Mycobacterium tuberculosis |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 15.04.2024 | ||
| 500 | |a Date Revised 15.04.2024 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Tuberculosis (TB) is the leading infectious disease caused by Mycobacterium tuberculosis and the second-most contagious killer after COVID-19. The emergence of drug-resistant TB has caused a great need to identify and develop new anti-TB drugs with novel targets. Indole propionic acid (IPA), a structural analog of tryptophan (Trp), is active against M. tuberculosis in vitro and in vivo. It has been verified that IPA exerts its antimicrobial effect by mimicking Trp as an allosteric inhibitor of TrpE, which is the first enzyme in the Trp synthesis pathway of M. tuberculosis. However, other Trp structural analogs, such as indolmycin, also target tryptophanyl-tRNA synthetase (TrpRS), which has two functions in bacteria: synthesis of tryptophanyl-AMP by catalyzing ATP + Trp and producing Trp-tRNATrp by transferring Trp to tRNATrp. So, we speculate that IPA may also target TrpRS. In this study, we found that IPA can dock into the Trp binding pocket of M. tuberculosis TrpRS (TrpRSMtb), which was further confirmed by isothermal titration calorimetry (ITC) assay. The biochemical analysis proved that TrpRS can catalyze the reaction between IPA and ATP to generate pyrophosphate (PPi) without Trp as a substrate. Overexpression of wild-type trpS in M. tuberculosis increased the MIC of IPA to 32-fold, and knock-down trpS in Mycolicibacterium smegmatis made it more sensitive to IPA. The supplementation of Trp in the medium abrogated the inhibition of M. tuberculosis by IPA. We demonstrated that IPA can interfere with the function of TrpRS by mimicking Trp, thereby impeding protein synthesis and exerting its anti-TB effect | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Indole propionic acid | |
| 650 | 4 | |a Mycobacterium tuberculosis | |
| 650 | 4 | |a protein synthesis | |
| 650 | 4 | |a tryptophan | |
| 650 | 4 | |a tryptophanyl-tRNA synthetase | |
| 650 | 7 | |a Tryptophan-tRNA Ligase |2 NLM | |
| 650 | 7 | |a EC 6.1.1.2 |2 NLM | |
| 650 | 7 | |a RNA, Transfer, Trp |2 NLM | |
| 650 | 7 | |a propionic acid |2 NLM | |
| 650 | 7 | |a JHU490RVYR |2 NLM | |
| 650 | 7 | |a Indoles |2 NLM | |
| 650 | 7 | |a Adenosine Triphosphate |2 NLM | |
| 650 | 7 | |a 8L70Q75FXE |2 NLM | |
| 650 | 7 | |a Propionates |2 NLM | |
| 700 | 1 | |a Gao, Yamin |e verfasserin |4 aut | |
| 700 | 1 | |a Zhou, Biao |e verfasserin |4 aut | |
| 700 | 1 | |a Hameed, H M Adnan |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Cuiting |e verfasserin |4 aut | |
| 700 | 1 | |a Ju, Yanan |e verfasserin |4 aut | |
| 700 | 1 | |a He, Jing |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Xiange |e verfasserin |4 aut | |
| 700 | 1 | |a Liu, Zhiyong |e verfasserin |4 aut | |
| 700 | 1 | |a Yu, Wei |e verfasserin |4 aut | |
| 700 | 1 | |a Xiong, Xiaoli |e verfasserin |4 aut | |
| 700 | 1 | |a Zhong, Nanshan |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Tianyu |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t ACS infectious diseases |d 2015 |g 10(2024), 4 vom: 12. Apr., Seite 1201-1211 |w (DE-627)NLM248280775 |x 2373-8227 |7 nnns |
| 773 | 1 | 8 | |g volume:10 |g year:2024 |g number:4 |g day:12 |g month:04 |g pages:1201-1211 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1021/acsinfecdis.3c00585 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 10 |j 2024 |e 4 |b 12 |c 04 |h 1201-1211 | ||