Polymyxins Bind to the Cell Surface of Unculturable Acinetobacter baumannii and Cause Unique Dependent Resistance

• Published in: Advanced science 2020-08, Vol.7 (15), p.2000704-n/a
• Main Authors: 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, Li, Jian
• Format: Article
• Language: English
• Subjects: Acinetobacter baumannii; membrane lipidomics; molecular dynamics; polymyxin; polymyxin‐dependent resistance
• ISSN: 2198-3844; 2198-3844
• DOI: 10.1002/advs.202000704

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. Herein, a mechanism of polymyxin‐dependent resistance in Acinetobacter baumannii is demonstrated. This unique dependence emerges only when i) the phosphatidylglycerol proportion in bacterial outer membrane increases to ≈35% and above, and ii) with ‘patch’ binding on the outer membrane by the rigid polymyxin molecules containing strong intramolecular hydrogen bonding, whereby polymyxin molecules enhance the membrane stability.