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The chronicity and recurrence of its infection pose serious challenges to public health. In this study, we reported that intracellular accumulation of \u03b1-ketoglutarate (\u03b1-KG) significantly increased ciprofloxacin (CIP) tolerance in MRSA. Using integrated metabolomic and functional genomic approaches, we demonstrated that both exogenous \u03b1-KG and genetic knockout of \u03b1-KG dehydrogenase (\u0394sucA, \u0394sucB) induced CIP tolerance in MRSA. Mechanistically, elevated \u03b1-KG levels drive the accumulation of glutamate (Glu), which in turn reduced bacterial membrane potential and cellular ATP content. Furthermore, Glu accumulation raised intracellular osmotic pressure, leading to decreased CIP uptake. These metabolic alterations enable MRSA to sustain high tolerance toward ciprofloxacin. Our findings reveal a key role of the \u03b1-KG-Glu metabolic axis in driving antibiotic tolerance and provide novel insights into the metabolic adaptations underlying drug persistence in MRSA.<\/jats:p>","DOI":"10.1021\/acs.jproteome.6c00131","type":"journal-article","created":{"date-parts":[[2026,8,4]],"date-time":"2026-08-04T14:04:22Z","timestamp":1785852262000},"page":"4636-4650","source":"Crossref","is-referenced-by-count":0,"title":["\u03b1-Ketoglutarate\nPromotes Ciprofloxacin\nTolerance in Methicillin-Resistant\n                    <i>Staphylococcus aureus<\/i>\n                    via Glutamate-Mediated Metabolic Remodeling"],"prefix":"10.1021","volume":"25","author":[{"given":"Qing-qiang","family":"Xu","sequence":"first","affiliation":[{"name":"South China Sea Institute of Oceanology, Chinese Academy of Sciences , , ,","place":["Guangzhou, China, 510301"]},{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lv-yuan","family":"Fan","sequence":"additional","affiliation":[{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing-yun","family":"Wu","sequence":"additional","affiliation":[{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhuo-ying","family":"Cao","sequence":"additional","affiliation":[{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-ting","family":"Zhang","sequence":"additional","affiliation":[{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-bin","family":"Su","sequence":"additional","affiliation":[{"name":"Jinan University , , ,","place":["Guangzhou, China, 510632"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4130-0806","authenticated-orcid":true,"given":"Jiao","family":"Fei","sequence":"additional","affiliation":[{"name":"South China Sea Institute of Oceanology, Chinese Academy of Sciences , , ,","place":["Guangzhou, China, 510301"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,7,31]]},"reference":[{"key":"2026090409134782300_cit1","doi-asserted-by":"publisher","first-page":"363","DOI":"10.25259\/JLP_200_2025","article-title":"Genomic epidemiology of antimicrobial\nresistance in Staphylococcus aureus: analysis of 1152 complete genomes","volume":"17","author":"Durairaj","year":"2025","journal-title":"J. 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