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Transcriptomic investigations of polymyxins and colistin/sulbactam combination against carbapenem-resistant Acinetobacter baumannii .

التفاصيل البيبلوغرافية
العنوان: Transcriptomic investigations of polymyxins and colistin/sulbactam combination against carbapenem-resistant Acinetobacter baumannii .
المؤلفون: Bian X; Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.; Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China.; National Health Commission & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.; Department of biological medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China.; Clinical Pharmacology Research Center, Huashan Hospital, Fudan University, Shanghai, China., Li M; Department of Critical Care Medicine, The Second Clinical Medical College, Jinan University (Shenzhen People's Hospital), Shenzhen, China.; Integrated Chinese and Western Medicine Postdoctoral Research Station, Jinan University, Guangzhou, China., Liu X; Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.; Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China.; National Health Commission & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China., Zhu Y; Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, China., Li J; Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Australia., Bergen PJ; Biomedicine Discovery Institute and Department of Microbiology, Monash University, Melbourne, Australia., Li W; Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.; Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China.; National Health Commission & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China., Li X; Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.; Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China.; National Health Commission & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China., Feng M; Department of biological medicines & Shanghai Engineering Research Center of Immunotherapeutics, School of Pharmacy, Fudan University, Shanghai, China., Zhang J; Institute of Antibiotics, Huashan Hospital, Fudan University, Shanghai, China.; Key Laboratory of Clinical Pharmacology of Antibiotics, Shanghai, China.; National Health Commission & National Clinical Research Center for Aging and Medicine, Huashan Hospital, Fudan University, Shanghai, China.; Clinical Pharmacology Research Center, Huashan Hospital, Fudan University, Shanghai, China.
المصدر: Computational and structural biotechnology journal [Comput Struct Biotechnol J] 2024 May 31; Vol. 23, pp. 2595-2605. Date of Electronic Publication: 2024 May 31 (Print Publication: 2024).
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology Country of Publication: Netherlands NLM ID: 101585369 Publication Model: eCollection Cited Medium: Print ISSN: 2001-0370 (Print) Linking ISSN: 20010370 NLM ISO Abbreviation: Comput Struct Biotechnol J Subsets: PubMed not MEDLINE
أسماء مطبوعة: Publication: Amsterdam : Elsevier B.V. on behalf of Research Network of Computational and Structural Biotechnology
Original Publication: Gothenburg, Sweden : Research Network of Computational and Structural Biotechnology
مستخلص: Carbapenem-resistant Acinetobacter baumannii (CRAB) is a Priority 1 (Critical) pathogen urgently requiring new antibiotics. Polymyxins are a last-line option against CRAB-associated infections. This transcriptomic study utilized a CRAB strain to investigate mechanisms of bacterial killing with polymyxin B, colistin, colistin B, and colistin/sulbactam combination therapy. After 4 h of 2 mg/L polymyxin monotherapy, all polymyxins exhibited common transcriptomic responses which primarily involved disruption to amino acid and fatty acid metabolism. Of the three monotherapies, polymyxin B induced the greatest number of differentially expressed genes (DEGs), including for genes involved with fatty acid metabolism. Gene disturbances with colistin and colistin B were highly similar (89 % common genes for colistin B), though effects on gene expression were generally lower (0-1.5-fold in most cases) with colistin B. Colistin alone (2 mg/L) or combined with sulbactam (64 mg/L) resulted in rapid membrane disruption as early as 1 h. Transcriptomic analysis of this combination revealed that the effects were driven by colistin, which included disturbances in fatty acid synthesis and catabolism, and inhibition of nutrient uptake. Combination therapy produced substantially higher fold changes in 72 % of DEGs shared with monotherapy, leading to substantially greater reductions in fatty acid biosynthesis and increases in biofilm, cell wall, and phospholipid synthesis. This indicates synergistic bacterial killing with the colistin/sulbactam combination results from a systematic increase in perturbation of many genes associated with bacterial metabolism. These mechanistic insights enhance our understanding of bacterial responses to polymyxin mono- and combination therapy and will assist to optimize polymyxin use in patients.
Competing Interests: None.
(© 2024 The Authors.)
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فهرسة مساهمة: Keywords: Carbapenem-resistant Acinetobacter baumannii; Combination; Polymyxins; Sulbactam; Transcriptomics
تواريخ الأحداث: Date Created: 20240715 Latest Revision: 20240716
رمز التحديث: 20240716
مُعرف محوري في PubMed: PMC11245955
DOI: 10.1016/j.csbj.2024.05.043
PMID: 39006922
قاعدة البيانات: MEDLINE
الوصف
تدمد:2001-0370
DOI:10.1016/j.csbj.2024.05.043