Getting Drugs through Small Pores: Exploiting the Porins Pathway in Pseudomonas aeruginosa.
Susruta SamantaIgor BodrenkoSilvia Acosta-GutiérrezTommaso D'AgostinoMonisha PathaniaIshan GhaiChristian SchlebergerDirk BumannRichard WagnerMathias WinterhalterBert van den BergMatteo CeccarelliPublished in: ACS infectious diseases (2018)
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 X-ray 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.
Keyphrases
- pseudomonas aeruginosa
- molecular dynamics simulations
- high resolution
- amino acid
- cystic fibrosis
- mass spectrometry
- biofilm formation
- single cell
- acinetobacter baumannii
- molecular docking
- gram negative
- high glucose
- ionic liquid
- diabetic rats
- drug induced
- neuropathic pain
- signaling pathway
- genome wide
- multidrug resistant
- structural basis
- high speed
- single molecule
- magnetic resonance
- magnetic resonance imaging
- escherichia coli
- oxidative stress
- spinal cord
- dna methylation
- spinal cord injury
- endothelial cells
- candida albicans
- liquid chromatography