期刊
ACS INFECTIOUS DISEASES
卷 4, 期 10, 页码 1519-1528出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsinfecdis.8b00149
关键词
outer membrane; porins; antibiotics transport; crystal structure; molecular simulations
资金
- TGCC [RA2699]
- Innovative Medicines Initiative Joint Undertaking [115525]
- European Union
- EFPIA
- EU FP7-PEOPLE-2013-ITN Translocation network [607694]
Understanding molecular properties of outer membrane channels of Gram-negative bacteria is of fundamental significance as they are the entry point of polar antibiotics into bacteria. Outer membrane proteomics revealed OccK8 (OprE) to be among the five most expressed substrate specific channels of the clinically important Pseudomonas aeruginosa. The high-resolution Xray structure and electrophysiology highlighted a very narrow pore. However, experimental in vitro methods showed the transport of natural amino acids and antibiotics, among them ceftazidime. We used molecular dynamics simulations to reveal the importance of the physicochemical properties of ceftazidime in modulating the translocation through OccK8, proposing a structure-function relationship. As in general porins, the internal electric field favors the translocation of polar molecules by gainful energy compensation in the central constriction region. Importantly, the comparatively narrow OccK8 pore can undergo a substrate induced expansion to accommodate relatively large-sized substrates.
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