Discovery of Potent Inhibitors of Streptococcus mutans Biofilm with Antivirulence Activity

Bhavitavya Nijampatnam, Parmanand Ahirwar, Piyasuda Pukkanasut, Holly Womack, Luke Casals, Hua Zhang, Xia Cai, Suzanne M. Michalek, Hui Wu, Sadanandan E. Velu

Research output: Contribution to journalArticlepeer-review

Abstract

Dental caries is a bacterial infectious disease characterized by demineralization of the tooth enamel. Treatment of this disease with conventional antibiotics is largely ineffective as the cariogenic bacteria form tenacious biofilms that are resistant to such treatments. The main etiological agent for dental caries is the bacterium Streptococcus mutans. S. mutans readily forms biofilms on the tooth surface and rapidly produces lactic acid from dietary sucrose. Glucosyl transferases (Gtfs) secreted by S. mutans are mainly responsible for the production of exopolysaccharides that are crucial for the biofilm architecture. Thus, inhibiting S. mutans' Gtfs is an effective approach to develop selective biofilm inhibitors that do not affect the growth of oral commensals. Herein, we report a library of 90 analogs of the previously identified lead compound, G43, and exploration of its structure activity relationships (SAR). All compounds were evaluated for the inhibition of S. mutans biofilms and bacterial growth. Selected compounds from this library were further evaluated for enzyme inhibition against Gtfs using a zymogram assay and for growth inhibition against oral commensal bacterial species such as Streptococcus gordonii and Streptococcus sanguinis. This study has led to the discovery of several new biofilm inhibitors with enhanced potency and selectivity. One of the leads, IIIF1, showed marked reduction in buccal, sulcal, and proximal caries scores in a rat model of dental caries.

Original languageEnglish (US)
Pages (from-to)48-55
Number of pages8
JournalACS Medicinal Chemistry Letters
Volume12
Issue number1
DOIs
StatePublished - Jan 14 2021

Keywords

  • Dental caries
  • SAR
  • Streptococcus mutans
  • biofilm
  • glucosyl transferases
  • in vivo

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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