Inhibitors of pathogen intercellular signals as selective anti-infective compounds

PLoS Pathog. 2007 Sep 14;3(9):1229-39. doi: 10.1371/journal.ppat.0030126.


Long-term antibiotic use generates pan-resistant super pathogens. Anti-infective compounds that selectively disrupt virulence pathways without affecting cell viability may be used to efficiently combat infections caused by these pathogens. A candidate target pathway is quorum sensing (QS), which many bacterial pathogens use to coordinately regulate virulence determinants. The Pseudomonas aeruginosa MvfR-dependent QS regulatory pathway controls the expression of key virulence genes; and is activated via the extracellular signals 4-hydroxy-2-heptylquinoline (HHQ) and 3,4-dihydroxy-2-heptylquinoline (PQS), whose syntheses depend on anthranilic acid (AA), the primary precursor of 4-hydroxy-2-alkylquinolines (HAQs). Here, we identified halogenated AA analogs that specifically inhibited HAQ biosynthesis and disrupted MvfR-dependent gene expression. These compounds restricted P. aeruginosa systemic dissemination and mortality in mice, without perturbing bacterial viability, and inhibited osmoprotection, a widespread bacterial function. These compounds provide a starting point for the design and development of selective anti-infectives that restrict human P. aeruginosa pathogenesis, and possibly other clinically significant pathogens.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology*
  • Anti-Bacterial Agents / therapeutic use
  • Cell Survival / physiology
  • Gene Expression Regulation, Bacterial
  • Mice
  • Mice, Inbred Strains
  • Pseudomonas Infections / drug therapy
  • Pseudomonas aeruginosa / genetics
  • Pseudomonas aeruginosa / physiology*
  • Quinolines / metabolism
  • Quorum Sensing / drug effects*
  • Quorum Sensing / physiology*
  • Virulence
  • Virus Cultivation
  • ortho-Aminobenzoates / chemistry
  • ortho-Aminobenzoates / metabolism


  • Anti-Bacterial Agents
  • Quinolines
  • ortho-Aminobenzoates
  • anthranilic acid