TY - JOUR
T1 - Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile
AU - Cao, Xinyun
AU - Boyaci, Hande
AU - Chen, James
AU - Bao, Yu
AU - Landick, Robert
AU - Campbell, Elizabeth A.
N1 - Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2022/4/21
Y1 - 2022/4/21
N2 - Fidaxomicin (Fdx) is widely used to treat Clostridioides difficile (Cdiff) infections, but the molecular basis of its narrow-spectrum activity in the human gut microbiome remains unknown. Cdiff infections are a leading cause of nosocomial deaths1. Fidaxomicin, which inhibits RNA polymerase, targets Cdiff with minimal effects on gut commensals, reducing recurrence of Cdiff infection2,3. Here we present the cryo-electron microscopy structure of Cdiff RNA polymerase in complex with fidaxomicin and identify a crucial fidaxomicin-binding determinant of Cdiff RNA polymerase that is absent in most gut microbiota such as Proteobacteria and Bacteroidetes. By combining structural, biochemical, genetic and bioinformatic analyses, we establish that a single residue in Cdiff RNA polymerase is a sensitizing element for fidaxomicin narrow-spectrum activity. Our results provide a blueprint for targeted drug design against an important human pathogen.
AB - Fidaxomicin (Fdx) is widely used to treat Clostridioides difficile (Cdiff) infections, but the molecular basis of its narrow-spectrum activity in the human gut microbiome remains unknown. Cdiff infections are a leading cause of nosocomial deaths1. Fidaxomicin, which inhibits RNA polymerase, targets Cdiff with minimal effects on gut commensals, reducing recurrence of Cdiff infection2,3. Here we present the cryo-electron microscopy structure of Cdiff RNA polymerase in complex with fidaxomicin and identify a crucial fidaxomicin-binding determinant of Cdiff RNA polymerase that is absent in most gut microbiota such as Proteobacteria and Bacteroidetes. By combining structural, biochemical, genetic and bioinformatic analyses, we establish that a single residue in Cdiff RNA polymerase is a sensitizing element for fidaxomicin narrow-spectrum activity. Our results provide a blueprint for targeted drug design against an important human pathogen.
UR - http://www.scopus.com/inward/record.url?scp=85127679302&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85127679302&partnerID=8YFLogxK
U2 - 10.1038/s41586-022-04545-z
DO - 10.1038/s41586-022-04545-z
M3 - Article
C2 - 35388215
AN - SCOPUS:85127679302
SN - 0028-0836
VL - 604
SP - 541
EP - 545
JO - Nature
JF - Nature
IS - 7906
ER -