Arginine catabolism is essential to polymyxin dependence in Acinetobacter baumannii

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dc.contributor.authorHan, MLen_AU
dc.contributor.authorAlsaadi, Yen_AU
dc.contributor.authorZhao, JXen_AU
dc.contributor.authorZhu, Yen_AU
dc.contributor.authorLu, Jen_AU
dc.contributor.authorJiang, Xen_AU
dc.contributor.authorMa, Wen_AU
dc.contributor.authorPatil, NAen_AU
dc.contributor.authorDunstan, RAen_AU
dc.contributor.authorLe Brun, APen_AU
dc.contributor.authorWickremasinghe, Hen_AU
dc.contributor.authorHu, Xen_AU
dc.contributor.authorWu, Yen_AU
dc.contributor.authorYu, HHen_AU
dc.contributor.authorWang, Jen_AU
dc.contributor.authorBarlow, CKen_AU
dc.contributor.authorBergen, PJen_AU
dc.contributor.authorShen, HHen_AU
dc.contributor.authorLithgow, Ten_AU
dc.contributor.authorCreek, DJen_AU
dc.contributor.authorVelkov, Ten_AU
dc.contributor.authorLi, Jen_AU
dc.date.accessioned2024-10-03T23:09:20Zen_AU
dc.date.available2024-10-03T23:09:20Zen_AU
dc.date.issued2024-07en_AU
dc.date.statistics2024-08-28en_AU
dc.description.abstractPolymyxins 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 licenceen_AU
dc.description.sponsorshipThis 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 (Womenโ€™s and Childrenโ€™s Hospital, Adelaide, Australia) for providing the bacterial strains.en_AU
dc.format.mediumPrint-Electronicen_AU
dc.identifier.articlenumber114410en_AU
dc.identifier.citationHan, 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.2024.114410en_AU
dc.identifier.issn2639-1856en_AU
dc.identifier.issn2211-1247en_AU
dc.identifier.issue7en_AU
dc.identifier.journaltitleCell Reportsen_AU
dc.identifier.urihttps://doi.org/10.1016/j.celrep.2024.114410en_AU
dc.identifier.urihttps://apo.ansto.gov.au/handle/10238/15720en_AU
dc.identifier.volume43en_AU
dc.languageEnglishen_AU
dc.language.isoenen_AU
dc.publisherElsevieren_AU
dc.subjectArginineen_AU
dc.subjectMetabolitesen_AU
dc.subjectMetabolismen_AU
dc.subjectMoleculesen_AU
dc.subjectGenesen_AU
dc.subjectCatabolismen_AU
dc.titleArginine catabolism is essential to polymyxin dependence in Acinetobacter baumanniien_AU
dc.typeJournal Articleen_AU
dcterms.dateAccepted2024-06-12en_AU
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