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Nat Prod Rep. 2019 Jan 1;36(1):220-247. doi: 10.1039/c8np00042e. Epub 2018 Jul 6.

Antibacterial properties and clinical potential of pleuromutilins.

Author information

1
Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA. seth.herzon@yale.edu.
2
Department of Chemistry, Yale University, New Haven, Connecticut 06520, USA. seth.herzon@yale.edu and Department of Pharmacology, Yale School of Medicine, New Haven, Connecticut 06520, USA.

Abstract

Covering: up to 2018Pleuromutilins are a clinically validated class of antibiotics derived from the fungal diterpene (+)-pleuromutilin (1). Pleuromutilins inhibit bacterial protein synthesis by binding to the peptidyl transferase center (PTC) of the ribosome. In this review we summarize the biosynthesis and recent total syntheses of (+)-pleuromutilin (1). We review the mode of interaction of pleuromutilins with the bacterial ribosome, which involves binding of the C14 extension and the tricyclic core to the P and A sites of the PTC, respectively. We provide an overview of existing clinical agents, and discuss the three primary modes of bacterial resistance (mutations in ribosomal protein L3, Cfr methylation, and efflux). Finally we collect structure-activity relationships from publicly available reports, and close with some forward looking statements regarding future development.

PMID:
29979463
DOI:
10.1039/c8np00042e
[Indexed for MEDLINE]

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