10'(Z),13'(E)-heptadecadienylhydroquinone Inhibits Swarming and Virulence Factors and Increases Polymyxin B Susceptibility in Proteus Mirabilis

PLoS One. 2012;7(9):e45563. doi: 10.1371/journal.pone.0045563. Epub 2012 Sep 20.

Abstract

In this study, we demonstrated that 10'(Z), 13'(E)-heptadecadienylhydroquinone (HQ17-2), isolated from the lacquer tree, could decrease swarming motility and hemolysin activity but increase polymyxin B (PB) susceptibilityof Proteus mirabilis which is intrinsically highly-resistant to PB. The increased PB susceptibility induced by HQ17-2 was also observed in clinical isolates and biofilm-grown cells. HQ17-2 could inhibit swarming in the wild-type and rppA mutant but not in the rcsB mutant, indicating that HQ17-2 inhibits swarming through the RcsB-dependent pathway, a two-component signaling pathway negatively regulating swarming and virulence factor expression. The inhibition of hemolysin activity by HQ17-2 is also mediated through the RcsB-dependent pathway, because HQ17-2 could not inhibit hemolysin activity in the rcsB mutant. Moreover, the finding that HQ17-2 inhibits the expression of flhDC gene in the wild-type and rcsB-complemented strain but not in the rcsB mutant supports the notion. By contrast, HQ17-2 could increase PB susceptibility in the wild-type and rcsB mutant but not in the rppA mutant, indicating that HQ17-2 increases PB susceptibility through the RppA-dependent pathway, a signaling pathway positively regulating PB resistance. In addition, HQ17-2 could inhibit the promoter activities of rppA and pmrI, a gene positively regulated by RppA and involved in PB resistance, in the wild-type but not in the rppA mutant. The inhibition of rppA and pmrI expression caused lipopolysaccharide purified from HQ17-2-treated cells to have higher affinity for PB. Altogether, this study uncovers new biological effects of HQ17-2 and provides evidence for the potential of HQ17-2 in clinical applications.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acyltransferases / genetics
  • Anti-Bacterial Agents / pharmacology*
  • Bacterial Proteins / genetics
  • Bacterial Proteins / metabolism
  • Drug Synergism
  • Gene Expression Regulation, Bacterial
  • Hemolysin Proteins / metabolism
  • Hydroquinones / pharmacology*
  • Microbial Sensitivity Tests
  • Mutation
  • Polymyxin B / pharmacology*
  • Promoter Regions, Genetic / drug effects
  • Proteus mirabilis / drug effects*
  • Proteus mirabilis / genetics*
  • Proteus mirabilis / metabolism
  • Signal Transduction
  • Virulence Factors* / genetics
  • Virulence Factors* / metabolism

Substances

  • 10'(Z),13'(E)-heptadecadienylhydroquinone
  • Anti-Bacterial Agents
  • Bacterial Proteins
  • Hemolysin Proteins
  • Hydroquinones
  • Virulence Factors
  • RcsB protein, Bacteria
  • Acyltransferases
  • flavanone synthetase
  • Polymyxin B

Grant support

This work was supported by grants from National Science Council (NSC 97-2320-B-002-025-MY3)and National Taiwan University Hospital, Taipei, Taiwan. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.