Synthetic Simplification of Carolacton Enables Chemical Genetic Studies in Streptococcus mutans

ACS Infect Dis. 2019 Aug 9;5(8):1480-1486. doi: 10.1021/acsinfecdis.9b00213. Epub 2019 Jun 25.

Abstract

Understanding the broader biological impact of carolacton, a macrolactone natural product, has been ongoing for the past decade. Multiple studies have shown connections to regulatory systems, acid tolerance mechanisms, biofilm formation, and recently folate dehydrogenase (FolD). Progress elucidating the cause of biofilm-specific activity in Streptococcus mutans has been limited due to low-throughput analyses of carolacton-treated cells. We disclose the discovery of a simplified carolacton-inspired analog that demonstrates inhibitory activity against S. mutans biofilm cells. This discovery permitted a proof of concept chemical genetic screen of S. mutans mutants identifying the carbon catabolite protein A signaling pathway as a putative target.

Keywords: antibiotic; bacterial biofilm; dental caries; diverted total synthesis; natural product.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Biofilms / drug effects*
  • Biofilms / growth & development
  • Biological Products / chemistry
  • Biological Products / pharmacology
  • Macrolides / chemistry*
  • Macrolides / pharmacology*
  • Microbial Sensitivity Tests
  • Mutation
  • Proof of Concept Study
  • Signal Transduction
  • Staphylococcal Protein A / metabolism
  • Streptococcus mutans / chemistry
  • Streptococcus mutans / drug effects*
  • Streptococcus mutans / genetics*

Substances

  • Biological Products
  • Macrolides
  • Staphylococcal Protein A
  • carolacton