@article{74ec0c2c0d834fa8902ee5646f4e0255,
title = "Arginine catabolism is essential to polymyxin dependence in Acinetobacter baumannii",
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.",
keywords = "CP: Metabolism, CP: Microbiology",
author = "Mei-Ling Han and Yasser Alsaadi and Jinxin Zhao and Yan Zhu and Jing Lu and Xukai Jiang and Wendong Ma and Patil, {Nitin A.} and Dunstan, {Rhys A.} and {Le Brun}, {Anton P.} and Hasini Wickremasinghe and Xiaohan Hu and Yimin Wu and Yu, {Heidi H.} and Jiping Wang and Barlow, {Christopher K.} and Bergen, {Phillip J.} and Hsin-Hui Shen and Trevor Lithgow and Creek, {Darren J.} and Tony Velkov and Jian Li",
note = "Funding Information: This research was supported by a research grant from the National Institute of Allergy and Infectious Disease (NIAID) of the National Institutes of Health (R01 AI132154). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIAID. The NR experiment was supported by the Australian Nuclear Science and Technology Organisation through proposal P13566. The Spatz neutron beam instrument operations are funded through the National Collaborative Research Infrastructure Strategy (NCRIS), an Australian government initiative. M.-L.H. is an Australian Research Council (ARC) DECRA Fellow (DE230100356). D.J.C. is an ARC Future Fellow. N.A.P. is an Australian National Health and Medical Research Council (NHMRC) Early Career Research Fellow. J. Li is an Australian NHMRC Principal Research Fellow. The authors would like to thank the Monash Proteomics and Metabolomics Facility (Monash University), the Monash Micromon Genomics Facility (Monash University), and the Australian Nuclear Science and Technology Organisation (ANSTO) for providing technical support. We appreciate Prof. Denis Spelman (Alfred Hospital, Melbourne, Australia) and Dr. Jan Bell and Prof. John Turnidge (Women's and Children's Hospital, Adelaide, Australia) for providing the bacterial strains. Conceptualization, M.-L.H. and J. Li; methodology, M.-L.H. Y.A. J.Z. X.J. R.A.D. C.K.B. D.J.C. and A.P.L.B.; investigation, M.-L.H. Y.A. J.Z. J. Lu, W.M. H.W. X.H. and Y.W.; resources, N.A.P. H.H.Y. and J.W.; formal analysis, M.-L.H. J.Z. and Y.Z.; writing \u2013 original draft, M.-L.H.; writing \u2013 review & editing, P.J.B. H.-H.S. T.L. D.J.C. T.V. and J. Li; supervision, J. Li; funding acquisition, J. Li. The authors declare no competing interests. Funding Information: This research was supported by a research grant from the National Institute of Allergy and Infectious Disease (NIAID) of the National Institutes of Health ( R01 AI132154 ). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIAID. The NR experiment was supported by the Australian Nuclear Science and Technology Organisation through proposal P13566 . The Spatz neutron beam instrument operations are funded through the National Collaborative Research Infrastructure Strategy (NCRIS) , an Australian government initiative. M.-L.H. is an Australian Research Council DECRA Fellow ( DE230100356 ). D.J.C. is an ARC Future Fellow. N.A.P. is an NHMRC Early Career Research Fellow. J.L. is an Australian National Health and Medical Research Council (NHMRC) Principal Research Fellow. The authors would like to thank the Monash Proteomics and Metabolomics Facility (Monash University), the Monash Micromon Genomics Facility (Monash University), and the Australian Nuclear Science and Technology Organization (ANSTO) for providing technical support. We appreciate Prof. Denis Spelman (Alfred Hospital, Melbourne, Australia) and Dr. Jan Bell and Prof. John Turnidge (Women\u2019s and Children\u2019s Hospital, Adelaide, Australia) for providing the bacterial strains. Publisher Copyright: {\textcopyright} 2024 The Author(s)",
year = "2024",
month = jul,
day = "23",
doi = "10.1016/j.celrep.2024.114410",
language = "English",
volume = "43",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Elsevier",
number = "7",
}