Origin of the Mobile Di-Hydro-Pteroate Synthase Gene Determining Sulfonamide Resistance in Clinical Isolates.

Sulfonamides are synthetic chemotherapeutic agents that work as competitive inhibitors of the di-hydro-pteroate synthase (DHPS) enzyme, encoded by the gene. Resistance to sulfonamides is widespread in the clinical setting and predominantly mediated by plasmid- and integron-borne genes encoding mutant DHPS enzymes that do not bind sulfonamides. In spite of their clinical importance, the genetic origin of genes remains unknown. Here we analyze genes and their genetic neighborhoods to uncover signature elements that enable the elucidation of their genetic origin. We identify a protein sequence Sul motif associated with -encoded proteins, as well as consistent association of a phosphoglucosamine mutase gene () with the gene. We identify chromosomal genes bearing these genetic markers in two bacterial families: the and the . Bayesian phylogenetic inference of FolP/Sul and GlmM protein sequences clearly establishes that and genes originated as a mobilization of genes present in, respectively, the and the , and indicate that the gene was transferred from the . Analysis of %GC content in / gene sequences supports the phylogenetic inference results and indicates that the emergence of the Sul motif in chromosomally encoded FolP proteins is ancient and considerably predates the clinical introduction of sulfonamides. assays reveal that both the and the , but not other related chromosomally encoded FolP proteins confer resistance in a sulfonamide-sensitive background, indicating that the Sul motif is associated with sulfonamide resistance. Given the absence of any known natural sulfonamides targeting DHPS, these results provide a novel perspective on the emergence of resistance to synthetic chemotherapeutic agents, whereby preexisting resistant variants in the vast bacterial pangenome may be rapidly selected for and disseminated upon the clinical introduction of novel chemotherapeuticals.