• Polymyxins bind to the cell surface of unculturable Acinetobacter baumannii and cause unique dependent resistance

Zhu, Yan, Lu, Jing, Han, Mei-Ling, Jiang, Xukai, Azad, Mohammad A. K., Patil, Nitin A., Lin, Yu-Wei, Zhao, Jinxin, Hu, Yang, Yu, Heidi H., Chen, Ke, Boyce, John D., Dunstan, Rhys A., Lithgow, Trevor, Barlow, Christopher K., Li, Weifeng, Schneider-Futschik, Elena K., Wang, Jiping, Gong, Bin, Sommer, Bjorn, Creek, Darren J., Fu, Jing, Wang, Lushan, Schreiber, Falk, Velkov, Tony and Li, Jian, 2020, Journal Article, Polymyxins bind to the cell surface of unculturable Acinetobacter baumannii and cause unique dependent resistance Advanced Science, 7 (15). pp. 1-13. ISSN 2198-3844

Abstract or Description:

Multidrug-resistant Acinetobacter baumannii is a top-priority pathogen globally and polymyxins are a last-line therapy. Polymyxin dependence in A. baumannii (i.e., nonculturable on agar without polymyxins) is a unique and highly-resistant phenotype with a significant potential to cause treatment failure in patients. The present study discovers that a polymyxin-dependent A. baumannii strain possesses mutations in both lpxC (lipopolysaccharide biosynthesis) and katG (reactive oxygen species scavenging) genes. Correlative multiomics analyses show a significantly remodeled cell envelope and remarkably abundant phosphatidylglycerol in the outer membrane (OM). Molecular dynamics simulations and quantitative membrane lipidomics reveal that polymyxin-dependent growth emerges only when the lipopolysaccharide-deficient OM distinctively remodels with ≥ 35% phosphatidylglycerol, and with “patch” binding on the OM by the rigid polymyxin molecules containing strong intramolecular hydrogen bonding. Rather than damaging the OM, polymyxins bind to the phosphatidylglycerol-rich OM and strengthen the membrane integrity, thereby protecting bacteria from external reactive oxygen species. Dependent growth is observed exclusively with polymyxin analogues, indicating a critical role of the specific amino acid sequence of polymyxins in forming unique structures for patch-binding to bacterial OM. Polymyxin dependence is a novel antibiotic resistance mechanism and the current findings highlight the risk of ‘invisible’ polymyxin-dependent isolates in the evolution of resistance.

Official URL: https://onlinelibrary.wiley.com/doi/full/10.1002/a...
Subjects: Other > Subjects allied to Medicine > B200 Pharmacology
Other > Biological Sciences > C700 Molecular Biology
School or Centre: School of Design
Funders: National Institute of Allergy and Infectious Diseases. Grant Numbers: R01 AI132154, AI132681, NHMRC, Australian Research Council
Identification Number or DOI: https://doi.org/10.1002/advs.202000704
Uncontrolled Keywords: Acinetobacter baumannii; membrane lipidomics; molecular dynamics; polymyxin; polymyxin-dependent resistance
Date Deposited: 08 Jul 2021 17:27
Last Modified: 08 Jul 2021 17:27
URI: https://researchonline.rca.ac.uk/id/eprint/4832
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