A roadmap for designing narrow-spectrum antibiotics targeting bacterial pathogens

Authors:

Xinyun Cao1,*, Robert Landick1,2, Elizabeth A. Campbell3

doi: 10.15698/mic2022.07.780
Volume 9, pp. 136 to 138, published 04/07/2022.

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Affiliations:

1Department of Biochemistry, University of Wisconsin-Madison; Madison, United States.
2Department of Bacteriology, University of Wisconsin-Madison; Madison, United States.
3Laboratory of Molecular Biophysics, The Rockefeller University; New York, United States.

Keywords: 

narrow-spectrum antibiotics, RNA polymerase, transcription, Clostridioides difficile, fidaxomicin

Corresponding Author(s):

Xinyun Cao, Department of Biochemistry, University of Wisconsin-Madison; Madison, United States xcao9@wisc.edu

Conflict of interest statement:

The authors declare no conflicts of interest.

Please cite this article as:

Xinyun Cao, Robert Landick, Elizabeth A. Campbell (2022). A roadmap for designing narrow-spectrum antibiotics targeting bacterial pathogens. Microbial Cell: 9(7): 136-138. doi: 10.15698/mic2022.07.780

© 2022 Can et al. This is an open-access article released under the terms of the Creative Commons Attribution (CC BY) license, which allows the unrestricted use, distribution, and reproduction in any medium, provided the original author and source are acknowledged.

Abstract:

Clostridioides difficile (Cdiff) infection (CDI) continues to be the leading threat of nosocomial deaths worldwide and a major burden on health-care systems. Broad-spectrum antibiotics eradicate the normal gut microbiome, killing protective commensal bacteria and increasing CDI recurrence. In contrast, Fidaxomicin (Fdx) is a narrow-spectrum antibiotic that inhibits Cdiff growth without affecting crucial gut microbes. However, the basis of the narrow-spectrum activity of Fdx on its target, RNA polymerase (RNAP), in Cdiff has been enigmatic. Recently, Cao et al. (Nature, DOI: 10.1038/s41586-022-04545-z) combined transgenic RNAP design and synthesis with cryo-electron microscopy (cryo-EM) to identify a key determinant of Fdx inhibition of Cdiff RNAP. This finding was further corroborated by biochemical, bioinformatics, and genetic analysis. This microreview describes implications of this work for lineage-specific antibiotic design and new directions toward understanding transcription and regulation in Cdiff and other bacterial pathogens.