(444h) Interaction of Small Molecules with Bacterial Outer Membrane Proteins

The presence of negatively charged outer membrane and the inner membrane makes the Gram-negative bacteria impermeable to a vast majority of potential antibiotics. Transport of solutes across the Gram-negative bacterial outer membrane occurs primarily through the water-filled porins. The transport selectivity is based not only on the substrate size and charge but also on the porins that have unique substrate binding sites to regulate the transport. In case of Pseudomonas aeruginosa, the uptake of nutrients a can only occur through substrate specific porins. There have been 19 porins identified thus far, and they have been divided into two subfamilies (OccD and OccK) that facilitate the transport of carboxylate-containing solutes. To quantify the transport of solutes, we have developed a computational platform that employs the X-ray structures of the Occ proteins to identify the substrate binding sites. Our work has been benchmarked against the carbapenem drugs that are most effective against P. aeruginosa. We have extended our work to modified carbapenems to narrow down the origin of chemical specificity and to identify the binding site for each porin. To achieve high-throughput screening and transport kinetics of the carbapenem and other small molecules, we have developed a highly parallelized algorithm for the known Occ proteins. Our work is focused on employing the high-throughput computational platform to investigate libraries of small molecules for enhanced permeability through the pathogenic Gram-negative bacteria with the long-term goal of identifying a new class of antibiotics.