scholarly journals Drug-like Fragments Inhibit agr-Mediated Virulence Expression in Staphylococcus aureus

2019 ◽  
Author(s):  
Ian F. Bezar ◽  
Ameya A. Mashruwala ◽  
Jeffrey M. Boyd ◽  
Ann M. Stock
Keyword(s):  
Staphylococcus Aureus ◽  
Biofilm Formation ◽  
Pathogenic Bacteria ◽  
Response Regulator ◽  
Virulence Gene ◽  
Drug Resistant ◽  
Virulence Gene Expression ◽  
Sensing System ◽  
Compound Libraries ◽  
Quorum Sensing System

In response to the increasingly problematic emergence of antibiotic resistance, novel strategies for combating pathogenic bacteria are being investigated. Targeting the agr quorum sensing system, which regulates expression of virulence in Staphylococcus aureus, is one potentially useful approach for combating drug-resistant pathogens that has not yet been fully explored. A previously published study of a fragment screen resulted in the identification of five compound fragments that interact with the DNA-binding domain of the response regulator AgrA from S. aureus. We have analyzed the ability of these compounds to affect agr-mediated virulence gene expression in S. aureus cells. Three of the compounds demonstrated the ability to reduce agr-driven transcription of at the P2 and P3 promoters of the agr operon and increase biofilm formation, and two of these compounds also showed the ability to reduce levels of secreted toxins. The finding that the compounds tested were able to reduce agr activity suggests that they could be useful tools for probing the effects of agr inhibition.Furthermore, the characteristics of compound fragments make them good starting materials for the development of compound libraries to iteratively improve the inhibitors.

scholarly journals Norlichexanthone Reduces Virulence Gene Expression and Biofilm Formation in Staphylococcus aureus

PLoS ONE ◽  
2016 ◽  
Vol 11 (12) ◽  
pp. e0168305 ◽  
Author(s):  
Mara Baldry ◽  
Anita Nielsen ◽  
Martin S. Bojer ◽  
Yu Zhao ◽  
Cathrine Friberg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Staphylococcus Aureus ◽  
Biofilm Formation ◽  
Virulence Gene ◽  
Virulence Gene Expression

scholarly journals Photo sensing and quorum sensing are integrated to control bacterial group behaviors

2019 ◽  
Author(s):  
Sampriti Mukherjee ◽  
Matthew Jemielita ◽  
Vasiliki Stergioula ◽  
Mikhail Tikhonov ◽  
Bonnie L. Bassler
Keyword(s):  
Quorum Sensing ◽  
Biofilm Formation ◽  
Response Regulator ◽  
Sensory Information ◽  
Virulence Gene ◽  
Component System ◽  
Virulence Gene Expression ◽  
Bacterial Phyla ◽  
Expression Of Genes ◽  
Genes Encoding

ABSTRACTPseudomonas aeruginosa transitions between the free-swimming state and the sessile biofilm mode during its pathogenic lifestyle. We show that quorum sensing represses P. aeruginosa biofilm formation and virulence by activating expression of genes encoding the KinB-AlgB two-component system. Phospho-AlgB represses biofilm and virulence genes, while KinB dephosphorylates, and thereby, inactivates AlgB. We discover that the photoreceptor BphP is the kinase that, in response to light, phosphorylates and activates AlgB. Indeed, exposing P. aeruginosa to light represses biofilm formation and virulence gene expression. To our knowledge, P. aeruginosa was not previously known to detect light. The KinB-AlgB-BphP module is present in all Pseudomonads, and we demonstrate that AlgB is the cognate response regulator for BphP in diverse bacterial phyla. We propose that KinB-AlgB-BphP constitutes a “three-component” system and AlgB is the node at which varied sensory information is integrated. This study sets the stage for light-mediated control of P. aeruginosa infectivity.

scholarly journals Novel Inhibitors of Staphylococcus aureus Virulence Gene Expression and Biofilm Formation

PLoS ONE ◽  
2012 ◽  
Vol 7 (10) ◽  
pp. e47255 ◽  
Author(s):  
Yibao Ma ◽  
Yuanxi Xu ◽  
Bryan D. Yestrepsky ◽  
Roderick J. Sorenson ◽  
Meng Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Staphylococcus Aureus ◽  
Biofilm Formation ◽  
Virulence Gene ◽  
Virulence Gene Expression

scholarly journals Identification of Novel Thermosensors in Gram-Positive Pathogens

2020 ◽  
Vol 7 ◽  
Author(s):  
Pilar Fernández ◽  
Alejandra Raquel Díaz ◽  
María Florencia Ré ◽  
Lucía Porrini ◽  
Diego de Mendoza ◽  
...  
Keyword(s):  
Pathogenic Bacteria ◽  
Response Regulator ◽  
Physiological Mechanism ◽  
Virulence Gene ◽  
Membrane Lipid ◽  
Gram Positive ◽  
Virulence Gene Expression ◽  
Cognate Response Regulator

Temperature is a crucial variable that every living organism, from bacteria to humans, need to sense and respond to in order to adapt and survive. In particular, pathogenic bacteria exploit host-temperature sensing as a cue for triggering virulence gene expression. Here, we have identified and characterized two integral membrane thermosensor histidine kinases (HKs) from Gram-positive pathogens that exhibit high similarity to DesK, the extensively characterized cold sensor histidine kinase from Bacillus subtilis. Through in vivo experiments, we demonstrate that SA1313 from Staphylococcus aureus and BA5598 from Bacillus anthracis, which likely control the expression of putative ATP binding cassette (ABC) transporters, are regulated by environmental temperature. We show here that these HKs can phosphorylate the non-cognate response regulator DesR, partner of DesK, both in vitro and in vivo, inducing in B. subtilis the expression of the des gene upon a cold shock. In addition, we report the characterization of another DesK homolog from B. subtilis, YvfT, also closely associated to an ABC transporter. Although YvfT phosphorylates DesR in vitro, this sensor kinase can only induce des expression in B. subtilis when overexpressed together with its cognate response regulator YvfU. This finding evidences a physiological mechanism to avoid cross talk with DesK after a temperature downshift. Finally, we present data suggesting that the HKs studied in this work appear to monitor different ranges of membrane lipid properties variations to mount adaptive responses upon cooling. Overall, our findings point out that bacteria have evolved sophisticated mechanisms to assure specificity in the response to environmental stimuli. These findings pave the way to understand thermosensing mediated by membrane proteins that could have important roles upon host invasion by bacterial pathogens.

scholarly journals RNAIII of the Staphylococcus aureus agr system activates global regulator MgrA by stabilizing mRNA

2015 ◽  
Vol 112 (45) ◽  
pp. 14036-14041 ◽  
Author(s):  
Ravi Kr. Gupta ◽  
Thanh T. Luong ◽  
Chia Y. Lee
Keyword(s):  
Staphylococcus Aureus ◽  
Biological Effects ◽  
Virulence Gene ◽  
Regulatory Function ◽  
Stable Complex ◽  
Global Regulator ◽  
Sensing System ◽  
Quorum Sensing System ◽  
P2 Promoter ◽  
Virulence Gene Regulation

RNAIII, the effector of the agr quorum-sensing system, plays a key role in virulence gene regulation in Staphylococcus aureus, but how RNAIII transcriptionally regulates its downstream genes is not completely understood. Here, we show that RNAIII stabilizes mgrA mRNA, thereby increasing the production of MgrA, a global transcriptional regulator that affects the expression of many genes. The mgrA gene is transcribed from two promoters, P1 and P2, to produce two mRNA transcripts with long 5′ UTR. Two adjacent regions of the mgrA mRNA UTR transcribed from the upstream P2 promoter, but not the P1 promoter, form a stable complex with two regions of RNAIII near the 5′ and 3′ ends. We further demonstrate that the interaction has several biological effects. We propose that MgrA can serve as an intermediary regulator through which agr exerts its regulatory function.

scholarly journals A Nonsense Mutation in agrA Accounts for the Defect in agr Expression and the Avirulence of Staphylococcus aureus 8325-4 traP::kan

2007 ◽  
Vol 75 (9) ◽  
pp. 4534-4540 ◽  
Author(s):  
Rajan P. Adhikari ◽  
Staffan Arvidson ◽  
Richard P. Novick
Keyword(s):  
Staphylococcus Aureus ◽  
Quorum Sensing ◽  
Mutant Strain ◽  
Nonsense Mutation ◽  
Stop Codon ◽  
Response Regulator ◽  
Wild Type ◽  
Sensing System ◽  
Quorum Sensing System ◽  
Type Sequence

ABSTRACT TraP is a triply phosphorylated staphylococcal protein that has been hypothesized to be the mediator of a second Staphylococcus aureus quorum-sensing system, “SQS1,” that controls expression of the agr system and therefore is essential for the organism's virulence. This hypothesis was based on the loss of agr expression and virulence by a traP mutant of strain 8325-4 and was supported by full complementation of both phenotypic defects by the cloned traP gene in strain NB8 (Y. Gov, I. Borovok, M. Korem, V. K. Singh, R. K. Jayaswal, B. J. Wilkinson, S. M. Rich, and N. Balaban, J. Biol. Chem. 279:14665-14672, 2004), in which the wild-type traP gene was expressed in trans in the 8325-4 traP mutant. We initiated a study of the mechanism by which TraP activates agr and found that the traP mutant strain used for this and other recently published studies has a second mutation, an adventitious stop codon in the middle of agrA, the agr response regulator. The traP mutation, once separated from the agrA defect by outcrossing, had no effect on agr expression or virulence, indicating that the agrA defect accounts fully for the lack of agr expression and for the loss of virulence attributed to the traP mutation. In addition, DNA sequencing showed that the agrA gene in strain NB8 (Gov et al., J. Biol. Chem., 2004), in contrast to that in the agr-defective 8325-4 traP mutant strain, had the wild-type sequence; further, the traP mutation in that strain, when outcrossed, also had no effect on agr expression.

scholarly journals Suppression of Staphylococcus aureus virulence by a small-molecule compound

2018 ◽  
Vol 115 (31) ◽  
pp. 8003-8008 ◽  
Author(s):  
Peng Gao ◽  
Pak Leung Ho ◽  
Bingpeng Yan ◽  
Kong Hung Sze ◽  
Julian Davies ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Small Molecule ◽  
Pathogenic Bacteria ◽  
Virulence Gene ◽  
Dependent Manner ◽  
Chemical Library ◽  
Virulence Gene Expression ◽  
Small Molecule Compound ◽  
Mouse Model Of Infection

Emerging antibiotic resistance among bacterial pathogens has necessitated the development of alternative approaches to combat drug-resistance-associated infection. The abolition of Staphylococcus aureus virulence by targeting multiple-virulence gene products represents a promising strategy for exploration. A multiplex promoter reporter platform using gfp-luxABCDE dual-reporter plasmids with selected promoters from S. aureus-virulence-associated genes was used to identify compounds that modulate the expression of virulence factors. One small-molecule compound, M21, was identified from a chemical library to reverse virulent S. aureus into its nonvirulent state. M21 is a noncompetitive inhibitor of ClpP and alters α-toxin expression in a ClpP-dependent manner. A mouse model of infection indicated that M21 could attenuate S. aureus virulence. This nonantibiotic compound has been shown to suppress the expression of multiple unrelated virulence factors in S. aureus, suggesting that targeting a master regulator of virulence is an effective way to control virulence. Our results illustrate the power of chemical genetics in the modulation of virulence gene expression in pathogenic bacteria.

Antibiofilm Effect of Adamantane Derivative against Staphylococcus aureus

2021 ◽  
Vol 83 (1) ◽  
pp. 58-67
Author(s):  
N.I. Hrynchuk ◽  
◽  
N.O. Vrynchanu ◽  
T.A. Buchtyarova ◽  
D.M. Dudikova ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Quorum Sensing ◽  
Biofilm Formation ◽  
Matrix Protein ◽  
Gentian Violet ◽  
Adamantane Derivative ◽  
Antibiofilm Activity ◽  
Antimicrobial Substances ◽  
Sensing System ◽  
Quorum Sensing System

Currently, one of the most urgent problems in clinical practice is the antibiotic therapy ineffectiveness at chronic diseases treatment caused by biofilms-forming microorganisms. One of the ways to its solution is the search for new compounds with antibiofilm activity which can prevent the adhesion of microorganisms, disrupt the structure of the biofilm matrix and affect the Quorum sensing system. The aim of the study was to investigate adamantane derivative 1-[4-(1-adamantyl) phenoxy]-3-(N-benzyl,N-dimethylamino)-2-propanol chloride (KVM-97) antimicrobial activity mechanism against Staphylococcus aureus biofilms. Methods. The ability of the adamantane derivative KVM-97 to prevent S. aureus biofilm formation and to destroy previously formed biofilms has been tested on polystyrene plates by gentian violet sorption on these structures, followed by desorption with organic solvent and use of resazurin (redox indicator). The S. aureus cells viability in mature biofilms was evaluated with specific dyes for living (acridine orange) and dead (propidium iodide) cells. Lowry method was used to assess the effect of KVM-97 on the matrix components for the total protein contents determination, the polysaccharides were detected spectrophotometrically (using phenol and sulfuric acid), Bap-protein – by test with Congo red. Persisters’ subpopulation was detected by activation of the SOS response in bacteria when exposed to high concentrations of antimicrobial substances. Results. It was found that KVM-97 (the compound with the adamantyl radical) showed an antibiofilm effect against S. aureus, decreasing biofilm biomass: at the biofilm formation stage – by 22.5% and 75.0%, while in case of 2-day biofilms treatment – by 34.5% and 32.4% at 0.5 MIC and 5.0 MIC respectively. Compound KVM-97 was able to reduce the number of metabolically active S. aureus cells only at the stage of biofilm formation (reduction by 92.7 and 95.8% at 2.0 and 5.0 MIC). Obtained results indicated that this adamantane-containing compound did not affect the protein and polysaccharides contents of S. aureus biofilms matrix. The changes of Bap-protein level caused by KVM-97 were not statistically significant (p>0.05). It was shown that KVM-97 did not prevent the formation of metabolically inactive persister cells; their share was 0.71% of the control. Conclusions. Thus, adamantane-containing compound KVM-97 is able to prevent S. aureus biofilm formation, causing significant biofilms’ mass reduction, as well as lowering the viable cells number in them and destroying already formed biofilms. Its antibiofilm effects are not associated with matrix protein and polysaccharides synthesis impairments. Further thorough investigations are needed to establish the effect of this compound on eDNA synthesis, the Quorum sensing system, and the ica and arg genes expression of S. aureus responsible for biofilm formation.

scholarly journals Salicylic acid stabilizes Staphylococcus aureus biofilm by impairing the agr quorum-sensing system

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Cristian Dotto ◽  
Andrea Lombarte Serrat ◽  
Martín Ledesma ◽  
Carlos Vay ◽  
Monika Ehling-Schulz ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Salicylic Acid ◽  
Quorum Sensing ◽  
Bacterial Cell ◽  
Biofilm Formation ◽  
Surfactant Molecule ◽  
Extracellular Dna ◽  
In Silico Docking ◽  
Sensing System ◽  
Quorum Sensing System

AbstractSalicylic acid (SAL) has recently been shown to induce biofilm formation in Staphylococcus aureus and to affect the expression of virulence factors. This study was aimed to investigate the effect of SAL on the regulatory agr system and its impact on S. aureus biofilm formation. The agr quorum-sensing system, which is a central regulator in S. aureus pathogenicity, plays a pivotal role in the dispersal of S. aureus mature biofilms and contributes to the creation of new colonization sites. Here, we demonstrate that SAL impairs biofilm dispersal by interfering with agr expression. As revealed by our work, protease and surfactant molecule production is diminished, and bacterial cell autolysis is also negatively affected by SAL. Furthermore, as a consequence of SAL treatment, the S. aureus biofilm matrix revealed the lack of extracellular DNA. In silico docking and simulation of molecular dynamics provided evidence for a potential interaction of AgrA and SAL, resulting in reduced activity of the agr system. In conclusion, SAL stabilized the mature S. aureus biofilms, which may prevent bacterial cell dissemination. However, it may foster the establishment of infections locally and consequently increase bacterial persistence leading to therapeutic failure.

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