Elucidating efflux inhibition and avoidance in $Pseudomonas aeruginosa$ through molecular-dynamics simulations.

Antibiotic resistance is a major threat to public health. Gram-negative pathogens, such as $Pseudomonas aeruginosa$, are of particular concern. One of the prevalent bacterial defence mechanisms is the active export of drugs out of the cell, mainly mediated by resistance-nodulation-division (RND) efflux pumps. The major RND efflux pump of $P. aeruginosa$ is MexAB-OprM, in which the inner membrane transporter MexB is responsible for recognition and binding of compounds. Due to the difficulty of producing co-crystals, computational methods are crucial to gaining insights into the interactions between compounds and MexB. We exploited multi-copy molecular-dynamics simulations to investigate the binding of peptidomimetics compounds to MexB. Based on microbiology studies, this series was shown to include efflux substrates, inhibitors, and avoiders. The detailed analysis of protein-ligand interactions (both direct and water-mediated) revealed characteristic patterns for each class of compounds, highlighting significant differences. Our results outline molecular-level information that could help the rational design of new inhibitors and new antibiotics less susceptible to the efflux mechanism.