l-Alanine specifically potentiates fluoroquinolone efficacy against Mycobacterium persisters via increased intracellular reactive oxygen species

The emergence and rapid spread of methicillin‐resistant Staphylococcus aureus (MRSA) raise a critical need for alternative therapeutic options. New antibacterial drugs and targets are required to combat MRSA‐associated infections. Based on this study, celastrol, a natural product from the roots of Tripterygium wilfordii Hook. f., effectively combats MRSA in vitro and in vivo. Multi‐omics analysis suggests that the molecular mechanism of action of celastrol may be related to Δ1‐pyrroline‐5‐carboxylate dehydrogenase (P5CDH). By comparing the properties of wild‐type and rocA‐deficient MRSA strains, it is demonstrated that P5CDH, the second enzyme of the proline catabolism pathway, is a tentative new target for antibacterial agents. Using molecular docking, bio‐layer interferometry, and enzyme activity assays, it is confirmed that celastrol can affect the function of P5CDH. Furthermore, it is found through site‐directed protein mutagenesis that the Lys205 and Glu208 residues are key for celastrol binding to P5CDH. Finally, mechanistic studies show that celastrol induces oxidative stress and inhibits DNA synthesis by binding to P5CDH. The findings of this study indicate that celastrol is a promising lead compound and validate P5CDH as a potential target for the development of novel drugs against MRSA.

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“…Therefore, celastrol affects DNA synthesis by affecting the production of ribose and purine. [ 76 , 77 ]…”

Section: Discussionmentioning

confidence: 99%

Celastrol Combats Methicillin‐Resistant Staphylococcus aureus by Targeting Δ¹‐Pyrroline‐5‐Carboxylate Dehydrogenase

Yuan

Wang

et al. 2023

Advanced Science

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“…Tuberculosis is caused by Mycobacterium tuberculosis, and it is a major health issue globally. A study discovered that exogenous L-alanine can lead to the manufacturing of reactive oxygen species in Mycobacterium smegmatis by accelerating the tricarboxylic Comparative analysis between rumen and duodenum 2 185 cid cycle and/or primary metabolism synergizing with fluoroquinolones, which, in the long run, results in the destruction of M. smegmatis (Zhen et al 2020).…”

Section: Discussionmentioning

confidence: 99%

Comparative Analysis of the Microbiota Between Rumen and Duodenum of Twin Lambs Based on Diets of Ceratoides or Alfalfa

Akonyani

Feng

Ying

et al. 2021

Polish Journal of Microbiology

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In our previous study, diet directly impacted the microbiota of the rumen in twin lambs. The duodenum is the first part of the small intestine, so we seek to determine whether there is a difference in the digesta between the two feed groups HFLP (high fiber, low protein) and LFHP (low fiber, high protein), and its impact on the biodiversity and metabolism of the duodenum. Results showed that the number of Operational Taxonomic Units (OTUs) in the duodenum (2,373 OTUs) was more than those in the rumen (1,230 OTUs), and 143 OTUs were significantly different in the duodenum between the two groups. The two most predominant phyla were Bacteriodetes and Firmicutes, but this ratio was reversed between the rumen and duodenum of lambs fed different feedstuffs. The difference in the digesta that greatly changed the biodiversity of the rumen and duodenum could affect the microbial community in the gastrointestinal tract (GIT). Sixteen metabolites were significantly different in the duodenum between the two groups based on the metabolome analysis. The relationships were built between the microbiome and the metabolome based on the correlation analysis. Some metabolites have a potential role in influencing meat quality, which indicated that the diet could affect the microbiota community and finally change meat quality. This study could explain how the diet affects the rumen and duodenum’s microbiota, lay a theoretical basis for controlling feed intake, and determine the relationship between the duodenum’s microbiota and metabolism.

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“…Altered amino acid metabolic pathways induced by exogenous amino acid supplementation in Escherichia coli ( 14 ) and Mycobacterium spp. ( 15 ) have been shown to affect oxidative stress and enhance endogenous reactive oxygen species (ROS) production in bacteria. ROS are key substances in balancing oxidative stress that occurs in bacteria ( 16 ).…”

Section: Introductionmentioning

confidence: 99%

“…Oxidative stress occurs when ROS accumulate to a certain level in bacteria and the produced hydroxyl radicals cause oxidative damage to cells by interacting with cellular components (lipids, DNA, and proteins) ( 17 ). Enhanced uptake of a drug by bacteria contributes to the induction of DNA damage, and the bactericidal effect of the drug on drug-resistant strains is subsequently enhanced ( 15 ). Therefore, we propose that exogenous metabolites may reduce drug tolerance in resistant strains if they promote bacterial DNA damage by increasing endogenous ROS levels.…”

Section: Introductionmentioning

confidence: 99%

Effects of l -Serine on Macrolide Resistance in Streptococcus suis

Wang

Dong

et al. 2022

Microbiol Spectr

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l-Alanine specifically potentiates fluoroquinolone efficacy against Mycobacterium persisters via increased intracellular reactive oxygen species

Cited by 3 publications

References 35 publications

Celastrol Combats Methicillin‐Resistant Staphylococcus aureus by Targeting Δ¹‐Pyrroline‐5‐Carboxylate Dehydrogenase

Celastrol Combats Methicillin‐Resistant Staphylococcus aureus by Targeting Δ¹‐Pyrroline‐5‐Carboxylate Dehydrogenase

Comparative Analysis of the Microbiota Between Rumen and Duodenum of Twin Lambs Based on Diets of Ceratoides or Alfalfa

Effects of l -Serine on Macrolide Resistance in Streptococcus suis

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l-Alanine specifically potentiates fluoroquinolone efficacy against Mycobacterium persisters via increased intracellular reactive oxygen species

Cited by 3 publications

References 35 publications

Celastrol Combats Methicillin‐Resistant Staphylococcus aureus by Targeting Δ1‐Pyrroline‐5‐Carboxylate Dehydrogenase

Celastrol Combats Methicillin‐Resistant Staphylococcus aureus by Targeting Δ1‐Pyrroline‐5‐Carboxylate Dehydrogenase

Comparative Analysis of the Microbiota Between Rumen and Duodenum of Twin Lambs Based on Diets of Ceratoides or Alfalfa

Effects of l -Serine on Macrolide Resistance in Streptococcus suis

Contact Info

Product

Resources

About

Celastrol Combats Methicillin‐Resistant Staphylococcus aureus by Targeting Δ¹‐Pyrroline‐5‐Carboxylate Dehydrogenase

Celastrol Combats Methicillin‐Resistant Staphylococcus aureus by Targeting Δ¹‐Pyrroline‐5‐Carboxylate Dehydrogenase