Metabolism-dependent succinylation governs resource allocation for antibiotic resistance.
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| Main Authors: | , , , , , |
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| Format: | Artículo científico |
| Language: | en |
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Science advances
2025
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| _version_ | 1868266162704351234 |
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| author | Wu, Jia-Han Chen, Xuan-Wei Liu, Ying-Li Wu, Jia-Yao Chen, Zhuang-Gui Peng, Bo |
| author_facet | Wu, Jia-Han Chen, Xuan-Wei Liu, Ying-Li Wu, Jia-Yao Chen, Zhuang-Gui Peng, Bo Wu, Jia-Han Chen, Xuan-Wei Liu, Ying-Li Wu, Jia-Yao Chen, Zhuang-Gui Peng, Bo |
| collection | PubMed - marine biology |
| contents | Metabolism-dependent succinylation governs resource allocation for antibiotic resistance. Wu, Jia-Han Chen, Xuan-Wei Liu, Ying-Li Wu, Jia-Yao Chen, Zhuang-Gui Peng, Bo Colistin Enterococcus faecalis Drug Resistance, Bacterial Glycerophospholipids Lipopolysaccharides Down-Regulation Phosphatidylethanolamines Bacterial Proteins Up-Regulation Triose-Phosphate Isomerase Glycolysis Protein Processing, Post-Translational The mechanisms that organisms allocate resources to sustain biological phenotypes remain largely unknown. Here, we use mobilized colistin resistance (), which modifies lipopolysaccharide (LPS) to confer colistin resistance, as a model to explore how bacteria reallocate resources to support -mediated resistance. We show that bacteria redirect resources from glycolysis, the pyruvate cycle, and LPS biosynthesis toward glycerophospholipid metabolism to produce phosphatidylethanolamine, the substrate for to modify LPS, while reducing LPS content to limit colistin binding. This reallocation down-regulates succinyl-coenzyme A (CoA) to diminish succinylation of proteins including triosephosphate isomerase (TPI), CpxR, and PdhR, thereby sustaining resistance. Exogenous succinate or α-ketoglutarate restores succinylation in a succinyl-CoA-dependent manner. Succinylation of TPI redirects metabolic flux to glycolysis and the pyruvate cycle, while succinylation of CpxR and PdhR up-regulates LPS biosynthesis, ultimately attenuating colistin resistance. Thus, we reveal a previously unrecognized mechanism by which bacteria regulate resource allocation through metabolism-driven posttranslational protein modification, offering strategies to combat antibiotic resistance. |
| format | Artículo científico |
| id | pubmed_40845110 |
| institution | PubMed |
| language | en |
| publishDate | 2025 |
| publisher | Science advances |
| record_format | pubmed |
| spellingShingle | Metabolism-dependent succinylation governs resource allocation for antibiotic resistance. Wu, Jia-Han Chen, Xuan-Wei Liu, Ying-Li Wu, Jia-Yao Chen, Zhuang-Gui Peng, Bo Colistin Enterococcus faecalis Drug Resistance, Bacterial Glycerophospholipids Lipopolysaccharides Down-Regulation Phosphatidylethanolamines Bacterial Proteins Up-Regulation Triose-Phosphate Isomerase Glycolysis Protein Processing, Post-Translational Metabolism-dependent succinylation governs resource allocation for antibiotic resistance. Wu, Jia-Han Chen, Xuan-Wei Liu, Ying-Li Wu, Jia-Yao Chen, Zhuang-Gui Peng, Bo Colistin Enterococcus faecalis Drug Resistance, Bacterial Glycerophospholipids Lipopolysaccharides Down-Regulation Phosphatidylethanolamines Bacterial Proteins Up-Regulation Triose-Phosphate Isomerase Glycolysis Protein Processing, Post-Translational The mechanisms that organisms allocate resources to sustain biological phenotypes remain largely unknown. Here, we use mobilized colistin resistance (), which modifies lipopolysaccharide (LPS) to confer colistin resistance, as a model to explore how bacteria reallocate resources to support -mediated resistance. We show that bacteria redirect resources from glycolysis, the pyruvate cycle, and LPS biosynthesis toward glycerophospholipid metabolism to produce phosphatidylethanolamine, the substrate for to modify LPS, while reducing LPS content to limit colistin binding. This reallocation down-regulates succinyl-coenzyme A (CoA) to diminish succinylation of proteins including triosephosphate isomerase (TPI), CpxR, and PdhR, thereby sustaining resistance. Exogenous succinate or α-ketoglutarate restores succinylation in a succinyl-CoA-dependent manner. Succinylation of TPI redirects metabolic flux to glycolysis and the pyruvate cycle, while succinylation of CpxR and PdhR up-regulates LPS biosynthesis, ultimately attenuating colistin resistance. Thus, we reveal a previously unrecognized mechanism by which bacteria regulate resource allocation through metabolism-driven posttranslational protein modification, offering strategies to combat antibiotic resistance. |
| title | Metabolism-dependent succinylation governs resource allocation for antibiotic resistance. |
| topic | Colistin Enterococcus faecalis Drug Resistance, Bacterial Glycerophospholipids Lipopolysaccharides Down-Regulation Phosphatidylethanolamines Bacterial Proteins Up-Regulation Triose-Phosphate Isomerase Glycolysis Protein Processing, Post-Translational |
| url | https://pubmed.ncbi.nlm.nih.gov/40845110/ |