Arginine catabolism is essential to polymyxin dependence in Acinetobacter baumannii
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Date
2024-07
Journal Title
Journal ISSN
Volume Title
Publisher
Elsevier
Abstract
Polymyxins are often the only effective antibiotics against the "Critical" pathogen Acinetobacter baumannii. Worryingly, highly polymyxin-resistant A. baumannii displaying dependence on polymyxins has emerged in the clinic, leading to diagnosis and treatment failures. Here, we report that arginine metabolism is essential for polymyxin-dependent A. baumannii. Specifically, the arginine degradation pathway was significantly altered in polymyxin-dependent strains compared to wild-type strains, with critical metabolites (e.g., L-arginine and L-glutamate) severely depleted and expression of the astABCDE operon significantly increased. Supplementation of arginine increased bacterial metabolic activity and suppressed polymyxin dependence. Deletion of astA, the first gene in the arginine degradation pathway, decreased phosphatidylglycerol and increased phosphatidylethanolamine levels in the outer membrane, thereby reducing the interaction with polymyxins. This study elucidates the molecular mechanism by which arginine metabolism impacts polymyxin dependence in A. baumannii, underscoring its critical role in improving diagnosis and treatment of life-threatening infections caused by "undetectable" polymyxin-dependent A. baumannii. ยช 2024 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY-NC licence
Description
Keywords
Arginine, Metabolites, Metabolism, Molecules, Genes, Catabolism
Citation
Han, M.-L., Alsaadi, Y., Zhao, J., Zhu, Y., Lu, J., Jiang, X., Ma, W., Patil, N. A., Dunstan, R. A., Le Brun, A. P., Wickremasinghe, H., Hu, X., Wu, Y., Yu, H. H., Wang, J., Barlow, C. K., Bergen, P. J., Shen, H.-H., Lithgow, T., Li, J. (2024). Arginine catabolism is essential to polymyxin dependence in Acinetobacter baumannii. Cell Reports, 43(7). doi:10.1016/j.celrep.2024.114410