2. Academic Validation
  3. Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile

Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile

  • Nature. 2022 Apr;604(7906):541-545. doi: 10.1038/s41586-022-04545-z.
Xinyun Cao  # 1,  Hande Boyaci  # 2,  James Chen 2,  Yu Bao 1,  Robert Landick 3 4,  Elizabeth A Campbell 5
Affiliations

Affiliations

  • 1 Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, United States.
  • 2 Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY, United States.
  • 3 Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, United States. rlandick@wisc.edu.
  • 4 Department of Bacteriology, University of Wisconsin-Madison, Madison, WI, United States. rlandick@wisc.edu.
  • 5 Laboratory of Molecular Biophysics, The Rockefeller University, New York, NY, United States. campbee@rockefeller.edu.
  • # Contributed equally.
PMID: 35388215 DOI: 10.1038/s41586-022-04545-z
Abstract

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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z