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<p>Microbial dysbiosis is the root cause for many diseases. The acidogenic <i>Streptococcus mutans (S.m.)</i> forms a exopolysaccharide-rich biofilm (EPS), mediated by species-specific glucosyltransferases (<i>Gtf</i>), which synthesizes both soluble and insoluble glucans directly on the bacterial surface. <i>GtfC</i> was selected as the primary druggable target since its activity is essential for biofilm initiation and cohesion. Commercial drugs were screened in silico against <i>GtfC</i>, followed by experimental biofilm assays. Two lead compounds, Radotinib and Pranlukast, significantly inhibited <i>GtfC</i> activity and reduced biofilm mass by up to 80. <i>GtfC</i> knock-out models confirmed biofilm disruption specifically via enzyme inhibition. Importantly, Radotinib selectively inhibited <i>S.m</i>. growth while preserving commensal species. This study identified at least two compounds capable of specifically inactivating a primary virulence factor of <i>S.m</i>. without inhibiting its growth, with a much lower selective pressure for drug resistance development, while simultaneously providing a growth advantage to commensal species that promote oral health.</p>

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Drug repurposing for glucosyltransferase inhibition for targeted oral biofilm disruption

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月16日

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  • Fernanda S. de Lucena,
  • Matthew G. Logan,
  • Steven H. Lewis,
  • Hua Zhang,
  • Matthew Barbisan,
  • Marcelo Y. Icimoto,
  • Hui Wu,
  • Dustin Higashi,
  • Justin L. Merritt,
  • Jonathon L. Baker,
  • Carmem S. Pfeifer

摘要

Microbial dysbiosis is the root cause for many diseases. The acidogenic Streptococcus mutans (S.m.) forms a exopolysaccharide-rich biofilm (EPS), mediated by species-specific glucosyltransferases (Gtf), which synthesizes both soluble and insoluble glucans directly on the bacterial surface. GtfC was selected as the primary druggable target since its activity is essential for biofilm initiation and cohesion. Commercial drugs were screened in silico against GtfC, followed by experimental biofilm assays. Two lead compounds, Radotinib and Pranlukast, significantly inhibited GtfC activity and reduced biofilm mass by up to 80. GtfC knock-out models confirmed biofilm disruption specifically via enzyme inhibition. Importantly, Radotinib selectively inhibited S.m. growth while preserving commensal species. This study identified at least two compounds capable of specifically inactivating a primary virulence factor of S.m. without inhibiting its growth, with a much lower selective pressure for drug resistance development, while simultaneously providing a growth advantage to commensal species that promote oral health.