Targeting Type IV pili as an antivirulence strategy against invasive meningococcal disease

Nat Microbiol. 2019 Jun;4(6):972-984. doi: 10.1038/s41564-019-0395-8. Epub 2019 Mar 25.


Bacterial virulence factors are attractive targets for the development of therapeutics. Type IV pili, which are associated with a remarkable array of properties including motility, the interaction between bacteria and attachment to biotic and abiotic surfaces, represent particularly appealing virulence factor targets. Type IV pili are present in numerous bacterial species and are critical for their pathogenesis. In this study, we report that trifluoperazine and related phenothiazines block functions associated with Type IV pili in different bacterial pathogens, by affecting piliation within minutes. Using Neisseria meningitidis as a paradigm of Gram-negative bacterial pathogens that require Type IV pili for pathogenesis, we show that piliation is sensitive to altered activity of the Na+ pumping NADH-ubiquinone oxidoreductase (Na+-NQR) complex and that these compounds probably altered the establishment of the sodium gradient. In vivo, these compounds exert a strong protective effect. They reduce meningococcal colonization of the human vessels and prevent subsequent vascular dysfunctions, intravascular coagulation and overwhelming inflammation, the hallmarks of invasive meningococcal infections. Finally, they reduce lethality. This work provides a proof of concept that compounds with activity against bacterial Type IV pili could beneficially participate in the treatment of infections caused by Type IV pilus-expressing bacteria.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / pharmacology
  • Blood Vessels / injuries
  • Blood Vessels / microbiology
  • Blood Vessels / pathology
  • Drug Combinations
  • Electron Transport Complex I
  • Female
  • Fimbriae, Bacterial / drug effects*
  • Fimbriae, Bacterial / genetics
  • Fimbriae, Bacterial / physiology*
  • Gene Expression Profiling
  • Gene Expression Regulation, Bacterial / drug effects
  • Gram-Negative Bacteria
  • Humans
  • Meningococcal Infections / prevention & control*
  • Mice
  • Neisseria meningitidis / drug effects*
  • Neisseria meningitidis / genetics
  • Neisseria meningitidis / growth & development
  • Phenothiazines / pharmacology
  • Skin / pathology
  • Skin Transplantation
  • Sodium-Potassium-Exchanging ATPase
  • Trifluoperazine / pharmacology
  • Virulence Factors*


  • Anti-Bacterial Agents
  • Drug Combinations
  • Phenothiazines
  • Virulence Factors
  • Trifluoperazine
  • Electron Transport Complex I
  • Sodium-Potassium-Exchanging ATPase