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Author Notes:

wwuest@emory.edu

We would like to acknowledge Dr. Robert J. Quivey (University of Rochester) and Dr. Bettina Buttaro (Temple University) for providing the bacterial strains used in this study, Materia, Inc. for catalysts, and Elana Shaw, Ashley Diaz, Jonathan Rosenfeld, and Zachary Chen (Emory University) for providing synthetic intermediates.

The authors declare no competing financial interest.

Subjects:

Research Funding:

Support was provided in part by the Emory University Integrated Cellular Imaging Microscopy Core. This research was supported by the National Science Foundation (CHE1755698) and the National Institute of Dental and Craniofacial Research (DE025837). The NMR instruments used in this work were supported by the National Science Foundation (CHE1531620).

Keywords:

  • antibiotic
  • natural product
  • dental caries
  • diverted total synthesis
  • bacterial biofilm

Synthetic Simplification of Carolacton Enables Chemical Genetic Studies in Streptococcus mutans

Tools:

Journal Title:

ACS Infectious Diseases

Volume:

Volume 5, Number 8

Publisher:

, Pages 1480-1486

Type of Work:

Article | Post-print: After Peer Review

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.
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