English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Sulfonamides are synthetic chemotherapeutic agents that work as competitive inhibitors of the di-hydro-pteroate synthase (DHPS) enzyme, encoded by the  folP  gene. Resistance to sulfonamides is widespread in the clinical setting and predominantly mediated by plasmid- and integron-borne  sul1-3  genes encoding mutant DHPS enzymes that do not bind sulfonamides. In spite of their clinical importance, the genetic origin of  sul1-3  genes remains unknown. Here we analyze  sul  genes and their genetic neighborhoods to uncover  sul  signature elements that enable the elucidation of their genetic origin. We identify a protein sequence Sul motif associated with  sul -encoded proteins, as well as consistent association of a phosphoglucosamine mutase gene ( glmM ) with the  sul2  gene. We identify chromosomal  folP  genes bearing these genetic markers in two bacterial families: the  Rhodobiaceae  and the  Leptospiraceae . Bayesian phylogenetic inference of FolP/Sul and GlmM protein sequences clearly establishes that  sul1-2  and  sul3  genes originated as a mobilization of  folP  genes present in, respectively, the  Rhodobiaceae  and the  Leptospiraceae , and indicate that the  Rhodobiaceae folP  gene was transferred from the  Leptospiraceae . Analysis of %GC content in  folP / sul  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.  In vitro  assays reveal that both the  Rhodobiaceae  and the  Leptospiraceae , but not other related chromosomally encoded FolP proteins confer resistance in a sulfonamide-sensitive  Escherichia coli  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.

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