| Autor: |
Yan Zhu, Jing Lu, Mei‐Ling Han, Xukai Jiang, Mohammad A. K. Azad, Nitin A. Patil, Yu‐Wei Lin, Jinxin Zhao, Yang Hu, Heidi H. Yu, Ke Chen, John D. Boyce, Rhys A. Dunstan, Trevor Lithgow, Christopher K. Barlow, Weifeng Li, Elena K. Schneider‐Futschik, Jiping Wang, Bin Gong, Bjorn Sommer, Darren J. Creek, Jing Fu, Lushan Wang, Falk Schreiber, Tony Velkov, Jian Li |
| Jazyk: |
angličtina |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
Advanced Science, Vol 7, Iss 15, Pp n/a-n/a (2020) |
| Druh dokumentu: |
article |
| ISSN: |
2198-3844 |
| DOI: |
10.1002/advs.202000704 |
| Popis: |
Abstract 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. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
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