Probing the binding affinities of imipenem and ertapenem for outer membrane carboxylate channel D1 (OccD1) from P. aeruginosa: simulation studies.

Pseudomonas aeruginosa is an important nosocomial human pathogen. The major difficulty in the fight against this pathogen is the relative impermeability of its outer membrane (OM). Only specific substrates can penetrate through the OM of P. aeruginosa via substrate-specific porins, so this has become one of the most problematic drug-resistant pathogens. Carbapenems are the most effective drugs for treating P. aeruginosa infections. One such carbapenem that is applied in cases of P. aeruginosa infection is imipenem (IMI), which uses outer membrane carboxylate channel D1 (OccD1) as a point of entry into the pathogen. Unlike IMI, ertapenem (ERTA, another carbapenem) shows only weak activity towards P. aeruginosa, as it is blocked from penetrating through the OM. However, it is currently unclear as to why IMI is allowed to pass through the OM while ERTA is not. Therefore, we conducted molecular dynamics (MD) simulations to elucidate the behavior of these drugs inside OccD1 as compared to the ligand-free state. We discovered another possible binding site in the constriction region close to the side-pore opening. Both drugs employ the core lactam part to tether themselves to the binding site, whereas the tail governs the direction of permeation. L132 and F133 appear to be involved in interactions that are key to core attachment. At least four hydrogen bonds are required for drug binding. The direction of motion of L2 also plays a role: inward flipping traps IMI in the constriction area, while a shift of L2 towards the membrane brings ERTA into contact with more water, which prompts the expulsion of ERTA to the mouth of the channel protein. The opening of L2 seems to facilitate the rejection of ERTA.