Infections due to Gram-negative bacteria and mycobacterium tuberculosis (Mtb) pose a serious threat to human health. These organisms produce especially complex cell envelopes consisting of a double layer of membranes that are essential for survival. This cell envelope also functions as a physical barrier to block entry of many classes of antibiotics and thereby render them ineffective. This research is directed towards understanding the structure and function of three protein transporters responsible for cell envelope assembly. Each of these transporters represents one of the three major transporter families, namely ABC transporters, MOPS transporters, and RND transporters. To understand how these transporters move their complex glycolipid cargo, biochemical and structural studies will be undertaken. Intermediates and inhibitors of transport and assembly of will be characterized structurally, biochemically, and in cells. A better understanding of these proteins? roles in cell envelope assembly will lead to new therapies to treat resistant infections.
The research proposed here is directed towards understanding the protein machinery responsible for the biogenesis of the cell envelopes of Gram-negative bacteria and mycobacterium tuberculosis. These multi- layered envelopes are essential for survival and provide intrinsic drug resistance. A better understanding of the lipid transporters that assemble the cell envelope may lead to the discovery of inhibitors that could ultimately be developed for therapeutic uses to treat drug-resistant infections.