Transport of Antibiotics through the Substrate Specific OprD Channel of Pseudomonas Aeruginosa

Abstract

Pseudomonas aeruginosa is a significant cause of nosocomial pneumonia and it is the most prevalent pathogen found in patients with severe injury or burns, where the associated mortality rate is up to 50%. Due to its poorly permeable outer membrane, P. aeruginosa shows strong resistance to a wide range of antibiotics. OprD is a specific porin for basic amino acids and apparently transports some carbapenems, a class of antibiotics with excellent activity against P. aeruginosa. However, there is little direct evidence for a specific binding-site for carbapenems within the OprD channel.With the help of biased molecular dynamics simulations, we aim to understand the structure and function of OprD at the molecular level and thus to elucidate the interaction of drug molecules with this channel. Our study suggests that the movement of loop L2 is a major factor governing ion transport through OprD. It has also been found out that the dynamics of loops L3 and L7 in the constriction region of the porin play a vital role in antibiotic transport as well as in the modulation of ion transport through OprD. The orientation of the carbapenem molecule is important for translocation of the molecule and this is influenced by the electrostatic effect of the basic ladder (constituting of ARG30, ARG39 ARG391 & ARG410) and negatively charged pocket (constituting of TYR176, TYR282 & ASP307) of OprD.Our study is not only helpful to understand the properties of OprD, but it also helps us to understand the properties of other members of the Outer membrane Carboxylic acid Channel (Occ) family. Representatives of this family, which show very high pairwise identity, are found in many pseudomonads and related bacteria.