Glutamine potentiates cefoperazone-sulbactam activity against Pseudomonas aeruginosa by increasing membrane permeability and cellular uptake
PurposesThe combination of an antibiotic with a metabolic reprogramming agent is anticipated to emerge as a promising therapeutic strategy against antibiotic-resistant bacteria, though this hypothesis requires validation through preclinical pharmacodynamic studies.MethodsThis study evaluated the pre...
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Frontiers Media S.A.
2025-07-01
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| Series: | Frontiers in Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fmicb.2025.1631646/full |
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| author | Jiao Xiang Xin Wang Huiyin Lin Lifen Yang Xiaoxia Huang Yuetao Chen Yingyue Zeng Shaohua Li Xianliang Zhao Shiwen Wang Yuan Tao Huanzhe Fu Zhengqi Shi Kuihai Wu Xuanxian Peng Hui Li Jin Tang Zhuanggui Chen |
| author_facet | Jiao Xiang Xin Wang Huiyin Lin Lifen Yang Xiaoxia Huang Yuetao Chen Yingyue Zeng Shaohua Li Xianliang Zhao Shiwen Wang Yuan Tao Huanzhe Fu Zhengqi Shi Kuihai Wu Xuanxian Peng Hui Li Jin Tang Zhuanggui Chen |
| author_sort | Jiao Xiang |
| collection | DOAJ |
| description | PurposesThe combination of an antibiotic with a metabolic reprogramming agent is anticipated to emerge as a promising therapeutic strategy against antibiotic-resistant bacteria, though this hypothesis requires validation through preclinical pharmacodynamic studies.MethodsThis study evaluated the preclinical pharmacodynamic profile of cefoperazone-sulbactam (SCF) combined with glutamine against Pseudomonas aeruginosa clinical isolates, including 54 antibiotic-sensitive (S-PA), 20 multidrug-resistant (MDR-PA), and 185 carbapenem-resistant strains (CR-PA).ResultsThe combination demonstrated synergistic efficacy in 251 cases (96.9%), equivalence in 7 (2.7%), and no interaction in 1 (0.4%) compared to SCF monotherapy. Time-kill assays, bacterial load quantification, and murine infection models consistently validated these findings, with therapeutic effects remaining stable by calcium concentrations and pH gradients. Glutamine slows the development of SCF resistance, delays the post-antibiotic effect, and reduces mutation frequency. Mechanistically, glutamine reprograms bacterial metabolism from an antibiotic-resistant to an antibiotic-sensitive state, thereby enhancing membrane permeability and increasing drug uptake. This accelerated drug influx surpasses the clearance capacity mediated by efflux pumps and enzymatic degradation, resulting in increased bacterial eradication.ConclusionThese findings suggest that the synergistic combination holds potential for developing therapeutic candidates against MDR-PA and CR-PA. |
| format | Article |
| id | doaj-art-86ce123721d4475e92f9a1de3ee4f977 |
| institution | Matheson Library |
| issn | 1664-302X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Microbiology |
| spelling | doaj-art-86ce123721d4475e92f9a1de3ee4f9772025-07-03T05:26:36ZengFrontiers Media S.A.Frontiers in Microbiology1664-302X2025-07-011610.3389/fmicb.2025.16316461631646Glutamine potentiates cefoperazone-sulbactam activity against Pseudomonas aeruginosa by increasing membrane permeability and cellular uptakeJiao Xiang0Xin Wang1Huiyin Lin2Lifen Yang3Xiaoxia Huang4Yuetao Chen5Yingyue Zeng6Shaohua Li7Xianliang Zhao8Shiwen Wang9Yuan Tao10Huanzhe Fu11Zhengqi Shi12Kuihai Wu13Xuanxian Peng14Hui Li15Jin Tang16Zhuanggui Chen17State Key Laboratory of Bio-Control, Third Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, ChinaHanzhong Central Hospital, Hanzhong, ChinaState Key Laboratory of Bio-Control, Third Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, ChinaState Key Laboratory of Bio-Control, Third Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, ChinaHanzhong Central Hospital, Hanzhong, ChinaState Key Laboratory of Bio-Control, Third Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, ChinaState Key Laboratory of Bio-Control, Third Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, ChinaState Key Laboratory of Bio-Control, Third Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, ChinaGuangdong Provincial Key Laboratory of Marine Biotechnology, Department of Biology, Shantou University, Shantou, ChinaState Key Laboratory of Bio-Control, Third Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, ChinaState Key Laboratory of Bio-Control, Third Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, ChinaState Key Laboratory of Bio-Control, Third Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, ChinaDepartment of Laboratory Medicine, The First People’s Hospital of Foshan, Foshan, ChinaDepartment of Laboratory Medicine, The First People’s Hospital of Foshan, Foshan, ChinaState Key Laboratory of Bio-Control, Third Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, ChinaState Key Laboratory of Bio-Control, Third Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, ChinaHanzhong Central Hospital, Hanzhong, ChinaState Key Laboratory of Bio-Control, Third Affiliated Hospital, School of Life Sciences, Sun Yat-sen University, Guangzhou, ChinaPurposesThe combination of an antibiotic with a metabolic reprogramming agent is anticipated to emerge as a promising therapeutic strategy against antibiotic-resistant bacteria, though this hypothesis requires validation through preclinical pharmacodynamic studies.MethodsThis study evaluated the preclinical pharmacodynamic profile of cefoperazone-sulbactam (SCF) combined with glutamine against Pseudomonas aeruginosa clinical isolates, including 54 antibiotic-sensitive (S-PA), 20 multidrug-resistant (MDR-PA), and 185 carbapenem-resistant strains (CR-PA).ResultsThe combination demonstrated synergistic efficacy in 251 cases (96.9%), equivalence in 7 (2.7%), and no interaction in 1 (0.4%) compared to SCF monotherapy. Time-kill assays, bacterial load quantification, and murine infection models consistently validated these findings, with therapeutic effects remaining stable by calcium concentrations and pH gradients. Glutamine slows the development of SCF resistance, delays the post-antibiotic effect, and reduces mutation frequency. Mechanistically, glutamine reprograms bacterial metabolism from an antibiotic-resistant to an antibiotic-sensitive state, thereby enhancing membrane permeability and increasing drug uptake. This accelerated drug influx surpasses the clearance capacity mediated by efflux pumps and enzymatic degradation, resulting in increased bacterial eradication.ConclusionThese findings suggest that the synergistic combination holds potential for developing therapeutic candidates against MDR-PA and CR-PA.https://www.frontiersin.org/articles/10.3389/fmicb.2025.1631646/fullpreclinical pharmacodynamicscefoperazone/sulbactammultidrug resistancecarbapenem resistanceglutaminePseudomonas aeruginosa |
| spellingShingle | Jiao Xiang Xin Wang Huiyin Lin Lifen Yang Xiaoxia Huang Yuetao Chen Yingyue Zeng Shaohua Li Xianliang Zhao Shiwen Wang Yuan Tao Huanzhe Fu Zhengqi Shi Kuihai Wu Xuanxian Peng Hui Li Jin Tang Zhuanggui Chen Glutamine potentiates cefoperazone-sulbactam activity against Pseudomonas aeruginosa by increasing membrane permeability and cellular uptake Frontiers in Microbiology preclinical pharmacodynamics cefoperazone/sulbactam multidrug resistance carbapenem resistance glutamine Pseudomonas aeruginosa |
| title | Glutamine potentiates cefoperazone-sulbactam activity against Pseudomonas aeruginosa by increasing membrane permeability and cellular uptake |
| title_full | Glutamine potentiates cefoperazone-sulbactam activity against Pseudomonas aeruginosa by increasing membrane permeability and cellular uptake |
| title_fullStr | Glutamine potentiates cefoperazone-sulbactam activity against Pseudomonas aeruginosa by increasing membrane permeability and cellular uptake |
| title_full_unstemmed | Glutamine potentiates cefoperazone-sulbactam activity against Pseudomonas aeruginosa by increasing membrane permeability and cellular uptake |
| title_short | Glutamine potentiates cefoperazone-sulbactam activity against Pseudomonas aeruginosa by increasing membrane permeability and cellular uptake |
| title_sort | glutamine potentiates cefoperazone sulbactam activity against pseudomonas aeruginosa by increasing membrane permeability and cellular uptake |
| topic | preclinical pharmacodynamics cefoperazone/sulbactam multidrug resistance carbapenem resistance glutamine Pseudomonas aeruginosa |
| url | https://www.frontiersin.org/articles/10.3389/fmicb.2025.1631646/full |
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