Design and characterization of a polyamine derivative inhibiting the expression of type III secretion system in Pseudomonas aeruginosa

The type III secretion system (TTSS) of Pseudomonas aeruginosa is a key virulence determinant for infection of eukaryotic hosts. Based on the findings that spermidine-mediated host-pathogen signalling is important for activation of type III secretion systems (TTSS), in this study, we designed, synthesized and evaluated a series of polyamine derivatives for their potentials in inhibiting the expression TTSS in P. aeruginosa. In vitro assay of 15 compounds synthesized in this study unveiled stringent structural requirements for TTSS-inhibitory activity. Among them, R101SPM, a conjugate between rhodamine 101 and spermine, showed a potent activity in inhibition of the TTSS gene expression and in attenuation of the TTSS-mediated cytotoxicity on human cells. In vivo analysis demonstrated that R101SPM could rescue mice from the lethal infection by P. aeruginosa. Moreover, genetic analysis showed that the full TTSS-inhibitory activity of R101SPM required a functional spermidine transporter. Taken together, our results present a new class of lead molecules for developing anti-virulence drugs and demonstrate that the spermidine transporter SpuDEGHF of P. aeruginosa is a promising drug target.

• Publication year

  2016

• Venue

  Scientific Reports

• Publication date

  2016-08-03

• Fields of study

  Biology, Medicine, Chemistry

• Identifiers
  DOI 10.1038/srep30949PMID 27484745PMCID 4971474
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Clinical features, risk factors, and outcomes of patients with interstitial pneumonia with autoimmune features: a population-based study

  2018cited by this paper
• A cell-cell communication signal integrates quorum sensing and stress response.

  2013cited by this paper
• Structural basis of substrate binding specificity revealed by the crystal structures of polyamine receptors SpuD and SpuE from Pseudomonas aeruginosa.

  2012cited by this paper
• Cis-2-dodecenoic acid receptor RpfR links quorum-sensing signal perception with regulation of virulence through cyclic dimeric guanosine monophosphate turnover

  2012cited by this paper
• Pseudoceramines A-D, new antibacterial bromotyrosine alkaloids from the marine sponge Pseudoceratina sp.

  2011cited by this paper
• A Darwinian Perspective on

  2011cited by this paper
• Discovery and Characterization of Inhibitors of Pseudomonas aeruginosa Type III Secretion

  2010cited by this paper
• Anti-virulence strategies to combat bacteria-mediated disease

  2010cited by this paper
• Mechanism of Transcriptional Activation by Pseudomonas aeruginosa ExsA

  2009cited by this paper
• Functional Domains of ExsA, the Transcriptional Activator of the Pseudomonas aeruginosa Type III Secretion System

  2009cited by this paper
• Alternating access in maltose transporter mediated by rigid-body rotations.

  2009cited by this paper
• Characterization of ExsA and of ExsA‐dependent promoters required for expression of the Pseudomonas aeruginosa type III secretion system

  2008cited by this paper
• Virulence blockers as alternatives to antibiotics: type III secretion inhibitors against Gram‐negative bacteria

  2008cited by this paper
• Small-Molecule Type III Secretion System Inhibitors Block Assembly of the Shigella Type III Secreton

  2008cited by this paper
• Modulation of Bacterial Type III Secretion System by a Spermidine Transporter Dependent Signaling Pathway

  2007cited by this paper
• Crystal structure of a catalytic intermediate of the maltose transporter

  2007cited by this paper
• Inhibition of Type III Secretion in Salmonella enterica Serovar Typhimurium by Small-Molecule Inhibitors

  2007cited by this paper
• Transcriptional regulation of the Pseudomonas aeruginosa type III secretion system

  2006cited by this paper
• Pandrug-resistant Pseudomonas aeruginosa among hospitalised patients: clinical features, risk-factors and outcomes.

  2006cited by this paper
• A small-molecule inhibitor of type III secretion inhibits different stages of the infectious cycle of Chlamydia trachomatis

  2006cited by this paper
• Two GacA-Dependent Small RNAs Modulate the Quorum-Sensing Response in Pseudomonas aeruginosa

  2006cited by this paper
• mini-Tn7 insertion in bacteria with secondary, non-glmS-linked attTn7 sites: example Proteus mirabilis HI4320

  2006cited by this paper
• Bioinformatics, genomics and evolution of non-flagellar type-III secretion systems: a Darwinian perspective.

  2005cited by this paper
• Small-Molecule Inhibitors Specifically Targeting Type III Secretion

  2005cited by this paper
• Lysophospholipase A activity of Pseudomonas aeruginosa type III secretory toxin ExoU.

  2004cited by this paper
• Coordinate regulation of bacterial virulence genes by a novel adenylate cyclase-dependent signaling pathway.

  2003cited by this paper
• The mechanism of action of the Pseudomonas aeruginosa‐encoded type III cytotoxin, ExoU

  2003cited by this paper
• Pseudomonas aeruginosa quorum sensing as a potential antimicrobial target.

  2003cited by this paper
• Characterization of Pseudomonas aeruginosa Exoenzyme S as a Bifunctional Enzyme in J774A.1 Macrophages

  2003cited by this paper
• Relative expression software tool (REST©) for group-wise comparison and statistical analysis of relative expression results in real-time PCR

  2002cited by this paper
• Molecular Cloning: A Laboratory Manual

  2001cited by this paper
• Type III protein secretion is associated with death in lower respiratory and systemic Pseudomonas aeruginosa infections.

  2001cited by this paper
• Pseudomonas aeruginosa ExoT Is a Rho GTPase-Activating Protein

  2000cited by this paper
• ExoT of Cytotoxic Pseudomonas aeruginosaPrevents Uptake by Corneal Epithelial Cells

  2000cited by this paper
• Cell-to-cell signaling and Pseudomonas aeruginosa infections.

  1998cited by this paper
• ExoY, an adenylate cyclase secreted by the Pseudomonas aeruginosa type III system.

  1998cited by this paper
• Cell-to-cell signaling and Pseudomonas aeruginosa infections.

  1998cited by this paper
• Intracellular targeting of exoenzyme S of Pseudomonas aeruginosa via type III‐dependent translocation induces phagocytosis resistance, cytotoxicity and disruption of actin microfilaments

  1997cited by this paper
• High efficiency electroporation of Pseudomonas aeruginosa using frozen cell suspensions.

  1990cited by this paper
• A Laboratory manual

  1989cited by this paper
• Isolation and characterization of transposon-induced mutants of Pseudomonas aeruginosa deficient in production of exoenzyme S

  1984cited by this paper
• Effect of pyochelin on the virulence of Pseudomonas aeruginosa

  1982cited by this paper
• Identification and Characterization of Small-Molecule Inhibitors of Yop Translocation in Yersinia pseudotuberculosis (cid:1)

  year unknowncited by this paper

• Genetic and Environmental Investigation of a Novel Phenylamino Acetamide Inhibitor of the Pseudomonas aeruginosa Type III Secretion System

  2022cites this paper
• Potential agrifood application of seriguela (Spondias purpurea L.) residues extract and nanoZnO as antimicrobial, antipathogenic and antivirulence agents

  2022cites this paper
• Spermidine Is an Intercellular Signal Modulating T3SS Expression in Pseudomonas aeruginosa

  2022cites this paper
• The Roles of Microbial Cell-Cell Chemical Communication Systems in the Modulation of Antimicrobial Resistance

  2020cites this paper
• Possible drugs for the treatment of bacterial infections in the future: anti-virulence drugs

  2020cites this paper
• On the road to structure-based development of anti-virulence therapeutics targeting the type III secretion system injectisome.

  2019cites this paper
• Synthesis and biological evaluation of 1,3,4-thiadiazole derivatives as type III secretion system inhibitors against Xanthomonas oryzae.

  2019cites this paper
• Crystal structure of SpuE-Spermidine in complex with ScFv5

  2019cites this paper
• Fitting Pieces into the Puzzle of Pseudomonas aeruginosa Type III Secretion System Gene Expression

  2019cites this paper
• Small Is Mighty-Chemical Communication Systems in Pseudomonas Aeruginosa.

  2019cites this paper
• A potent anti-SpuE antibody allosterically inhibits type III secretion system and attenuates virulence of Pseudomonas aeruginosa.

  2019cites this paper
• ASC acts in a caspase‐1‐independent manner to worsen acute pneumonia caused by Pseudomonas aeruginosa

  2018cites this paper
• Immunological blocking of spermidine‐mediated host–pathogen communication provides effective control against Pseudomonas aeruginosa infection

  2018cites this paper
• Human Salivary Protein Histatin 5 Has Potent Bactericidal Activity against ESKAPE Pathogens

  2017cites this paper
• Design, Synthesis, and Biological Evaluation of Mitochondria-Targeted Flavone-Naphthalimide-Polyamine Conjugates with Antimetastatic Activity.

  2017cites this paper
• Thymol-Based Inhibition of Biofilm and Type III Secretion System Thymol-Based Inhibition of Biofilm and Type III Secretion System as a Potential Alternative Therapy for Pseudomonas Aeruginosa as a Potential Alternative Therapy for Pseudomonas Aeruginosa Infections Infections

  year unknowncites this paper