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The extraordinary capacity in fine-tuning the metabolic states enables its success in tolerance to antibiotics and evading host immune defenses. However, the linkage among transcriptional regulation, metabolic states and antibiotic tolerance in P. aeruginosa remains largely unclear. By screening the P. aeruginosa TF mutant library constructed by CRISPR\/Cas12k-guided transposase, we identify that rccR (PA5438) is a major genetic determinant in aminoglycoside antibiotic tolerance, the deletion of which substantially enhances bacterial tolerance. We further reveal the inhibitory roles of RccR in pyruvate metabolism (aceE\/F) and glyoxylate shunt pathway (aceA and glcB), and overexpression of aceA or glcB enhances bacterial tolerance. Moreover, we identify that 2-keto-3-deoxy-6-phosphogluconate (KDPG) is a signal molecule that directly binds to RccR. Structural analysis of the RccR\/KDPG complex reveals the detailed interactions. Substitution of the key residue\u00a0R152, K270 or R277 with alanine abolishes KDPG sensing by RccR and impairs bacterial growth with glycerol or glucose as the sole carbon source. Collectively, our study unveils the connection between aminoglycoside antibiotic tolerance and RccR-mediated central carbon metabolism regulation in P. aeruginosa, and elucidates the KDPG-sensing mechanism by RccR.<\/jats:p>","DOI":"10.1093\/nar\/gkad1201","type":"journal-article","created":{"date-parts":[[2023,12,5]],"date-time":"2023-12-05T12:20:04Z","timestamp":1701778804000},"page":"967-976","source":"Crossref","is-referenced-by-count":15,"title":["A KDPG sensor RccR governs\n                    <i>Pseudomonas aeruginosa<\/i>\n                    carbon metabolism and aminoglycoside antibiotic tolerance"],"prefix":"10.1093","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1806-0004","authenticated-orcid":false,"given":"Yujue","family":"Wang","sequence":"first","affiliation":[{"name":"School of Physical Science and Technology, ShanghaiTech University , Shanghai\u00a0 201210 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhipeng","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology, ShanghaiTech University , Shanghai\u00a0 201210 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weizhong","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology, ShanghaiTech University , Shanghai\u00a0 201210 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ze-Hui","family":"Ren","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University , Guangzhou\u00a0 510275 , Guangdong , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Gao","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology, ShanghaiTech University , Shanghai\u00a0 201210 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiani","family":"Dai","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology, ShanghaiTech University , Shanghai\u00a0 201210 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6797-9319","authenticated-orcid":false,"given":"Guan-Zheng","family":"Luo","sequence":"additional","affiliation":[{"name":"MOE Key Laboratory of Gene Function and Regulation, Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, State Key Laboratory of Biocontrol, School of Life Sciences, Sun Yat-sen University , Guangzhou\u00a0 510275 , Guangdong , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaowei","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology, ShanghaiTech University , Shanghai\u00a0 201210 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2321-8462","authenticated-orcid":false,"given":"Quanjiang","family":"Ji","sequence":"additional","affiliation":[{"name":"School of Physical Science and Technology, ShanghaiTech University , Shanghai\u00a0 201210 , China"},{"name":"Gene Editing Center, School of Life Science and Technology, ShanghaiTech University , Shanghai\u00a0 201210 , China"},{"name":"Shanghai Clinical Research and Trial Center , Shanghai\u00a0 201210 , China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,12,14]]},"reference":[{"key":"2024012516153414800_B1","doi-asserted-by":"crossref","first-page":"351","DOI":"10.2165\/00003495-200767030-00003","article-title":"The epidemiology, pathogenesis and treatment of Pseudomonas aeruginosa infections","volume":"67","author":"Driscoll","year":"2007","journal-title":"Drugs"},{"key":"2024012516153414800_B2","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1128\/AAC.49.2.479-487.2005","article-title":"Aminoglycoside resistance in Pseudomonas aeruginosa","volume":"49","author":"Poole","year":"2005","journal-title":"Antimicrob. 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