The periplasmic protein TolB as a potential drug target in Pseudomonas aeruginosa

PLoS One. 2014 Aug 5;9(8):e103784. doi: 10.1371/journal.pone.0103784. eCollection 2014.

Abstract

The Gram-negative bacterium Pseudomonas aeruginosa is one of the most dreaded pathogens in the hospital setting, and represents a prototype of multi-drug resistant "superbug" for which effective therapeutic options are very limited. The identification and characterization of new cellular functions that are essential for P. aeruginosa viability and/or virulence could drive the development of anti-Pseudomonas compounds with novel mechanisms of action. In this study we investigated whether TolB, the periplasmic component of the Tol-Pal trans-envelope protein complex of Gram-negative bacteria, represents a potential drug target in P. aeruginosa. By combining conditional mutagenesis with the analysis of specific pathogenicity-related phenotypes, we demonstrated that TolB is essential for P. aeruginosa growth, both in laboratory and clinical strains, and that TolB-depleted P. aeruginosa cells are strongly defective in cell-envelope integrity, resistance to human serum and several antibiotics, as well as in the ability to cause infection and persist in an insect model of P. aeruginosa infection. The essentiality of TolB for P. aeruginosa growth, resistance and pathogenicity highlights the potential of TolB as a novel molecular target for anti-P. aeruginosa drug discovery.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Bacterial Agents / therapeutic use*
  • Drug Discovery*
  • Drug Resistance, Bacterial / genetics
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Targeted Therapy*
  • Organisms, Genetically Modified
  • Periplasmic Proteins / isolation & purification
  • Periplasmic Proteins / physiology*
  • Polymyxins / therapeutic use
  • Pseudomonas Infections / drug therapy*
  • Pseudomonas aeruginosa / genetics*
  • Pseudomonas aeruginosa / growth & development
  • Pseudomonas aeruginosa / pathogenicity*

Substances

  • Anti-Bacterial Agents
  • Periplasmic Proteins
  • Polymyxins

Grant support

Regina Fernández-Piñar is supported by a Post-doc fellowship from the Fundación Alfonso Martín Escudero (Spain). The work on essential periplasmic proteins in Francesco Imperi's laboratory is supported by a grant from the Pasteur Institute-Cenci Bolognetti Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.