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... OF FIGURES Figure 3. Effect of benzbromarone on staphyloxanthin production and bacterial autolysis in LAC USA300 and LAC ∆agr mutant........................................................................................ 97 Staphylococcus aureus, a common colonizer of the human skin and mucosa, can cause illnesses ranging from minor skin infections and abscesses to life-threatening diseases such as necrotizing pneumonia, endocarditis, and septicemia (Lowy, 1998). ...
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... B binds the secreted AIPs and prevents them from binding to the receptor, AgrC, inhibiting quorum sensing and subsequent production of downstream virulence factors ( Peterson et al., 2008). These two host factors in addition to the inactivation of AIPs by reactive oxygen species (Rothfork et al., 2004) are three ways the host inhibits quorum sensing-dependent virulence factor production by S. aureus ( Figure 3). ...
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... benzbromarone inhibited stationary phase growth and staphyloxanthin is produced in late stationary phase, we determined the effect of benzbromarone on staphyloxanthin production. We documented the production of staphyloxanthin over time by photographs and quantified the amount of pigment by methanol extraction in LAC USA300 ( Figure 3A) and LAC USA300 ∆agr mutant ( Figure 3B). The pictures of Figure 3A-B illustrate that as staphyloxanthin was produced, the addition of benzbromarone in the culture inhibited the production of the pigment in both the LAC wild type and the ∆agr mutant strain. ...
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... benzbromarone inhibited stationary phase growth and staphyloxanthin is produced in late stationary phase, we determined the effect of benzbromarone on staphyloxanthin production. We documented the production of staphyloxanthin over time by photographs and quantified the amount of pigment by methanol extraction in LAC USA300 ( Figure 3A) and LAC USA300 ∆agr mutant ( Figure 3B). The pictures of Figure 3A-B illustrate that as staphyloxanthin was produced, the addition of benzbromarone in the culture inhibited the production of the pigment in both the LAC wild type and the ∆agr mutant strain. ...
Context 5
... documented the production of staphyloxanthin over time by photographs and quantified the amount of pigment by methanol extraction in LAC USA300 ( Figure 3A) and LAC USA300 ∆agr mutant ( Figure 3B). The pictures of Figure 3A-B illustrate that as staphyloxanthin was produced, the addition of benzbromarone in the culture inhibited the production of the pigment in both the LAC wild type and the ∆agr mutant strain. This was confirmed by quantification of the pigment. ...
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... we cultured LAC or ∆agr mutant for 18 hr in the presence or absence of benzbromarone before washing and resuspending in the autolysis buffer (50mM glycine supplemented with Triton X-100). As shown in Figure 3C and 3D, the addition of benzbromarone decreased the rate of autolysis over the course of a 28 hr assay in both the LAC wild type and the ∆agr mutant. These data suggest that benzbromarone prevents the bacterial cells from lysing and the resulting production of eDNA. ...
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In recent years, Pseudomonas aeruginosa emerged as a significant pathogenic microorganism in the majority of hospital-acquired infections due to the elevated levels of resistance to antibacterial agents by virtue of its highly organized quorum sensing (QS). P. aeruginosa has three hierarchical major QS systems (LasI/R, RhlI/R, and PqsA/R) that are...
[This corrects the article on p. 1733 in vol. 7, PMID: 27877157.].
Pseudomonas aeruginosa (Pae) is an opportunistic human pathogen, able to resist host defense mechanisms and antibiotic treatment. In Pae, the master regulator of stress responses RpoS (σS) is involved in the regulation of quorum sensing and several virulence genes. Here, we report that the sRNA ReaL translationally silences rpoS mRNA, which results...
Quorum sensing (QS) is a form of cooperative social behaviour which relies on extracellular signalling molecules that elicit the QS response across many cells and controls the development of many cooperative traits including biofilm formation. The main aim of this work is to review the published work on cooperative social behaviour of Bacillus subt...
Citations
... This led to the identification of benzbromarone (compound 2, Fig. 2C), which was previously used to treat gout. Benzbromarone appear to have a much more global effect on S. aureus, affecting not only RNAIII transcription, but also staphyloxanthin synthesis [40]. In addition, it also inhibits late stationary phase growth, suggesting more efforts are needed for improving the specificity. ...
Background:
The increasing threats of antibiotic resistance urge the need for developing new approaches to combat bacterial infections including those caused by Staphylococcus aureus (S. aureus). Unlike conventional antibiotics that aim to kill bacteria or inhibit their growth, targeting bacterial virulence may be a promising alternative approach, which imposes less selective pressure for antibiotic resistance in future generations.
Objective:
Our goal is to provide a systematic review about developing high-throughput screening (HTS) strategies for the identification of inhibitors targeting virulence of S. aureus. We also describe an overview of virulence regulatory pathways for potential antivirulence targets.
Methods:
We focus on five potential targets or target families, including agr quorum sensing system, SarA/MgrA protein family, sortase A, Clp protease and eukaryotic-like Ser/Thr phosphatase (Stp1). For each target, we introduce its role in virulence regulation, summarize the HTS approaches that are used to identify novel anti-virulence inhibitors, and discuss the advantages and disadvantages of these strategies.
Conclusion:
The discovery of anti-virulence inhibitors via HTS underlines the promising potential of anti-virulence therapy for S. aureus. The development of HTS strategies can facilitate the identification of novel anti-virulence inhibitors for combating S. aureus infection, and may also advance our understanding on virulence regulation in S. aureus.
Quorum sensing (QS) is a cell density-dependent regulatory system that orchestrates the group behavior of unicellular organisms by synchronizing the expression of certain gene(s) within the clonal community of same species. Bacterial pathogens often employ QS system to establish efficiently an infection. A large part of low GC Gram-positive bacteria belonging to phylum Firmicutes use thiolactone/lactone peptides as communication signals so-called autoinducing peptides (AIPs) to coordinate QS circuit. In particular, QS of staphylococci, enterococci, and clostridia have been intensively studied in terms of alternative target of anti-pathogenic chemotherapy independent of bactericidal antibiotics. Thus far, a number of quorum quenching (QQ) agents that targeting the QS circuit of these Gram-positive pathogens have been developed by random screening of natural compounds or rationale design of AIP antagonists. This review summarizes those QQ agents and previews their potential as post-antibiotic drugs.
Virulence gene expression in Staphylococcus aureus is tightly regulated by intricate networks of transcriptional regulators and two-component signal transduction systems. There is now an emerging body of evidence to suggest that the blockade of S. aureus virulence gene expression significantly attenuates infection in experimental models. In this perspective, we will provide insights into medicinal chemistry strategies for the development of chemical reagents that have the capacity to inhibit staphylococcal virulence expression. These reagents can be broadly grouped into four categories: (1) competitive inhibitors of the accessory gene regulator (agr) quorum sensing system, (2) inhibitors of AgrA-DNA interactions, (3) RNAIII transcription inhibitors, and (4) inhibitors of the SarA family of transcriptional regulators. We discuss the potential of specific examples of anti-virulence agents for the management and treatment of staphylococcal infections.
