Multidrug Resistance: Phylogenetic Characterization of Superfamilies of Secondary Carriers that Include Drug Exporters

We here describe the application of novel programs that allow definition of phylogenetic relationships in transport protein superfamilies. These programs are used to provide information about the four major superfamilies of secondary carriers that include members that export hydrophobic and amphipathic compounds including drugs. These novel programs must be used when sequence divergence among superfamily members is too great to allow construction of reliable multiple alignments. We test the validity and demonstrate the reliability of these trees by conducting comparative analyses. We examine all of the largest superfamilies of secondary drug efflux pumps found in nature, the MOP, DMT, RND, and MFS superfamilies. Depending on the superfamily, phylogenetic clustering of the families and individual members of these families can occur according to organismal source, substrate type, polarity of transport, and/or mode of transport. In this chapter we define the phylogenetic relationships of sequence divergent drug exporters. The programs developed should be applicable to all classes of proteins and nucleic acids.