scholarly journals Staphylococcus aureus Responds to the Central Metabolite Pyruvate To Regulate Virulence

mBio ◽  
2018 ◽  
Vol 9 (1) ◽  
Author(s):  
Lamia Harper ◽  
Divya Balasubramanian ◽  
Elizabeth A. Ohneck ◽  
William E. Sause ◽  
Jessica Chapman ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Responses ◽  
Virulence Factors ◽  
Regulatory Networks ◽  
Metabolic Flux ◽  
Bacterial Pathogen ◽  
Strong Relationship ◽  
Global Changes ◽  
Human Pathogens ◽  
Environmental Signals

ABSTRACTStaphylococcus aureusis a versatile bacterial pathogen that can cause significant disease burden and mortality. Like other pathogens,S. aureusmust adapt to its environment to produce virulence factors to survive the immune responses evoked by infection. Despite the importance of environmental signals forS. aureuspathogenicity, only a limited number of these signals have been investigated in detail for their ability to modulate virulence. Here we show that pyruvate, a central metabolite, causes alterations in the overall metabolic flux ofS. aureusand enhances its pathogenicity. We demonstrate that pyruvate induces the production of virulence factors such as the pore-forming leucocidins and that this induction results in increased virulence of community-acquired methicillin-resistantS. aureus(CA-MRSA) clone USA300. Specifically, we show that an efficient “pyruvate response” requires the activation ofS. aureusmaster regulators AgrAC and SaeRS as well as the ArlRS two-component system. Altogether, our report further establishes a strong relationship between metabolism and virulence and identifies pyruvate as a novel regulatory signal for the coordination of theS. aureusvirulon through intricate regulatory networks.IMPORTANCEDelineation of the influence of host-derived small molecules on the makeup of human pathogens is a growing field in understanding host-pathogen interactions.S. aureusis a prominent pathogen that colonizes up to one-third of the human population and can cause serious infections that result in mortality in ~15% of cases. Here, we show that pyruvate, a key nutrient and central metabolite, causes global changes to the metabolic flux ofS. aureusand activates regulatory networks that allow significant increases in the production of leucocidins. These and other virulence factors are critical forS. aureusto infect diverse host niches, initiate infections, and effectively subvert host immune responses. Understanding how environmental signals, particularly ones that are essential to and prominent in the human host, affect virulence will allow us to better understand pathogenicity and consider more-targeted approaches to tackling the currentS. aureusepidemic.

scholarly journals MODERN APPROACHES TO ANTIVIRULENT THERAPY OF DISEASES ASSOCIATED WITH STAPHYLOCOCCUS AUREUS

2019 ◽  
Vol 23 (3-4) ◽  
pp. 26-31
Author(s):  
T.O. Kryuchko ◽  
O.Ya. Tkachenko ◽  
N.V. Kuzmenko ◽  
I.N. Nesina ◽  
S.M. Tanianska ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Bacterial Infections ◽  
Effective Means ◽  
Bacterial Pathogen ◽  
Cross Reactivity ◽  
Main Function ◽  
Virulence Proteins ◽  
New Antibiotics ◽  
Active Research

Staphylococcus aureus is a universal bacterial pathogen, which is able to develop the resistance to new antibiotics, by means of virulence factors, whose main function is the spread of diseases by inhibiting the immune factors of host defense. Its wide spread at in-patient departments and also the presence of clinical probationary wards Staphylococcus aureus, resistant to methicillin at out-patient departments, deprive the doctors of effective means for control of the infection. Complications caused by MRSA lead to hospitalization and indices of lethality. The aim of the paper is to analyze the main factors of S. аureus virulence and ways the of its interaction as a result of etiological and pathogenetic treatment. Complexity of treatment of bacterial infections is determined by alternative ways of prevention and treatment of diseases to which bacteria are not able to develop resistance. Along with general mechanisms that form antibiotic resistance, S. aureus produces many individual virulence factors that model the immune response, affecting the survival of the microorganism. The virulence factors produced by S. aureus are diverse and have the ability not only to cause cell lysis, but also to stimulate tissue rejection and destruction. It is important to determine that many specific factors of virulence caused by S. aureus, have ability to change both congenital and adaptive immune reactions including inhibition of complement activation, neutrophils neutralization, phagocytes inhibition. Strategies for inhibiting virulence factors can range from using small inhibitor molecules or full-fledged antibodies to creating toxoids and virulence proteins. Great interest is focused upon those inhibitors that have cross-reactivity with respect to multiple virulence factors, as well as inhibitors, the main target of which is a global regulator with multi-purpose activity, for example, agr operon. Active research into the specific alternative antivirulent treatments for severe diseases caused by S. aureus can potentially settle a number of problems and difficulties of post-antibiotic era.

scholarly journals Candida albicans and Staphylococcus aureus Pathogenicity and Polymicrobial Interactions: Lessons beyond Koch’s Postulates

2019 ◽  
Vol 5 (3) ◽  
pp. 81 ◽  
Author(s):  
Olivia A. Todd ◽  
Brian M Peters
Keyword(s):  
Staphylococcus Aureus ◽  
Candida Albicans ◽  
Sequence Data ◽  
Bacterial Pathogen ◽  
Toxin Production ◽  
Microbial Interactions ◽  
Human Pathogens ◽  
Koch’S Postulates ◽  
Bacterial Interaction ◽  
Koch's Postulates

While Koch’s Postulates have established rules for microbial pathogenesis that have been extremely beneficial for monomicrobial infections, new studies regarding polymicrobial pathogenesis defy these standards. The explosion of phylogenetic sequence data has revolutionized concepts of microbial interactions on and within the host. However, there remains a paucity of functional follow-up studies to delineate mechanisms driven by such interactions and how they shape health or disease. That said, one particular microbial pairing, the fungal opportunist Candida albicans and the bacterial pathogen Staphylococcus aureus, has received much attention over the last decade. Therefore, the objective of this review is to discuss the multi-faceted mechanisms employed by these two ubiquitous human pathogens during polymicrobial growth, including how they: establish and persist in inter-Kingdom biofilms, tolerate antimicrobial therapy, co-invade host tissue, exacerbate quorum sensing and staphylococcal toxin production, and elicit infectious synergism. Commentary regarding new challenges and remaining questions related to future discovery of this fascinating fungal–bacterial interaction is also provided.

scholarly journals Inactivation of Phospholipase D Diminishes Acinetobacter baumannii Pathogenesis

2010 ◽  
Vol 78 (5) ◽  
pp. 1952-1962 ◽  
Author(s):  
Anna C. Jacobs ◽  
Indriati Hood ◽  
Kelli L. Boyd ◽  
Patrick D. Olson ◽  
John M. Morrison ◽  
...  
Keyword(s):  
Acinetobacter Baumannii ◽  
Virulence Factors ◽  
Phospholipase D ◽  
Cell Invasion ◽  
Regulatory Networks ◽  
Bacterial Pathogen ◽  
Ventilator Associated Pneumonia ◽  
Mutant Library ◽  
Strain Background ◽  
Epithelial Cell Invasion

ABSTRACT Acinetobacter baumannii is an emerging bacterial pathogen of considerable health care concern. Nonetheless, relatively little is known about the organism's virulence factors or their regulatory networks. Septicemia and ventilator-associated pneumonia are two of the more severe forms of A. baumannii disease. To identify virulence factors that may contribute to these disease processes, genetically diverse A. baumannii clinical isolates were evaluated for the ability to proliferate in human serum. A transposon mutant library was created in a strain background that propagated well in serum and screened for members with decreased serum growth. The results revealed that disruption of A. baumannii phospholipase D (PLD) caused a reduction in the organism's ability to thrive in serum, a deficiency in epithelial cell invasion, and diminished pathogenesis in a murine model of pneumonia. Collectively, these results suggest that PLD is an A. baumannii virulence factor.

scholarly journals Structure-Based Functional Characterization of Repressor of Toxin (Rot), a Central Regulator of Staphylococcus aureus Virulence

2014 ◽  
Vol 197 (1) ◽  
pp. 188-200 ◽  
Author(s):  
April Killikelly ◽  
Meredith A. Benson ◽  
Elizabeth A. Ohneck ◽  
Jared M. Sampson ◽  
Jean Jakoncic ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Dna Binding ◽  
Virulence Factors ◽  
Regulatory Networks ◽  
Functional Characterization ◽  
Site Directed Mutagenesis ◽  
Binding Motif ◽  
Content Type ◽  
Specific Effects ◽  
Target Promoters

Staphylococcus aureusis responsible for a large number of diverse infections worldwide. In order to support its pathogenic lifestyle,S. aureushas to regulate the expression of virulence factors in a coordinated fashion. One of the central regulators of theS. aureusvirulence regulatory networks is the transcription factor repressor of toxin (Rot). Rot plays a key role in regulatingS. aureusvirulence through activation or repression of promoters that control expression of a large number of critical virulence factors. However, the mechanism by which Rot mediates gene regulation has remained elusive. Here, we have determined the crystal structure of Rot and used this information to probe the contribution made by specific residues to Rot function. Rot was found to form a dimer, with each monomer harboring a winged helix-turn-helix (WHTH) DNA-binding motif. Despite an overall acidic pI, the asymmetric electrostatic charge profile suggests that Rot can orient the WHTH domain to bind DNA. Structure-based site-directed mutagenesis studies demonstrated that R91, at the tip of the wing, plays an important role in DNA binding, likely through interaction with the minor groove. We also found that Y66, predicted to bind within the major groove, contributes to Rot interaction with target promoters. Evaluation of Rot binding to different activated and repressed promoters revealed that certain mutations on Rot exhibit promoter-specific effects, suggesting for the first time that Rot differentially interacts with target promoters. This work provides insight into a precise mechanism by which Rot controls virulence factor regulation inS. aureus.

scholarly journals Nusbiarylins Inhibit Transcription and Target Virulence Factors in Bacterial Pathogen Staphylococcus aureus

2020 ◽  
Vol 21 (16) ◽  
pp. 5772
Author(s):  
Adrian Jun Chu ◽  
Yangyi Qiu ◽  
Rachel Harper ◽  
Lin Lin ◽  
Cong Ma ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Antimicrobial Agents ◽  
Bacterial Pathogen ◽  
Cellular Respiration ◽  
Regulatory Pathways ◽  
Protein Levels ◽  
Transcription Inhibitors ◽  
Bacterial Transcription

The emergence of multidrug resistance in the clinically significant pathogen Staphylococcus aureus is a global health burden, compounded by a diminishing drug development pipeline, and a lack of approved novel antimicrobials. Our previously reported first-in-class bacterial transcription inhibitors “nusbiarylins” presented a promising prospect towards the discovery of novel antimicrobial agents with a novel mechanism. Here we investigated and characterised the lead nusbiarylin compound, MC4, and several of its chemical derivatives in both methicillin-resistant S. aureus (MRSA) and the S. aureus type strains, demonstrating their capacity for the arrest of growth and cellular respiration, impairment of RNA and intracellular protein levels at subinhibitory concentrations. In some instances, derivatives of MC4 were also shown to attenuate the production of staphylococcal virulence factors in vitro, such as the exoproteins α-toxin and Panton–Valentine Leukocidin (PVL). Trends observed from quantitative PCR assays suggested that nusbiarylins elicited these effects possibly by acting via but not limited to the modulation of global regulatory pathways, such as the agr regulon, which coordinates the expression of S. aureus genes associated with virulence. Our findings encourage the continued development of more potent compounds within this novel family of bacterial transcription inhibitors.

scholarly journals Requirement of Signal Peptidase ComC and Thiol-Disulfide Oxidoreductase DsbA for Optimal Cell Surface Display of Pseudopilin ComGC in Staphylococcus aureus

2012 ◽  
Vol 78 (19) ◽  
pp. 7124-7127 ◽  
Author(s):  
Magdalena M. van der Kooi-Pol ◽  
Ewoud Reilman ◽  
Mark J. J. B. Sibbald ◽  
Yanka K. Veenstra-Kyuchukova ◽  
Thijs R. H. M. Kouwen ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Surface ◽  
Virulence Factors ◽  
Surface Display ◽  
Bacterial Pathogen ◽  
Cell Surface Display ◽  
Signal Peptidase ◽  
Gram Positive ◽  
Content Type ◽  
Disulfide Oxidoreductase

ABSTRACTStaphylococcus aureusis an important Gram-positive bacterial pathogen producing many secreted and cell surface-localized virulence factors. Here we report that the staphylococcal thiol-disulfide oxidoreductase DsbA is essential for stable biogenesis of the ComGC pseudopilin. The signal peptidase ComC is indispensable for ComGC maturation and optimal cell surface exposure.

scholarly journals Antivirulence effects of pomegranate peel extracts on most common urinary tract infection pathogens in pregnant women

2016 ◽  
Vol 1 (4) ◽  
pp. 7 ◽  
Author(s):  
Wafaa Sadeq Al-Wazni ◽  
Bashair Sami Hadi
Keyword(s):  
Staphylococcus Aureus ◽  
Urinary Tract Infection ◽  
Urinary Tract ◽  
Tract Infection ◽  
Virulence Factors ◽  
Pathogenic Bacteria ◽  
Bacterial Pathogen ◽  
Pomegranate Peel ◽  
Alcohol Extract ◽  
Inhibition Zones

Objective This study includes the investigation of antibacterial and antivirulence activities of three types of pomegranate peel extracts andthen determines the interaction between the extracts and antibiotic in vitro.Methods The ability of most common isolated bacteria from urinary tract infection (UTI) to produce different virulence factors were testedand the effect of plant extracts on virulence factors were determined; in addition the correlation between extracts and antibiotics wereevaluated by using fractional inhibitory concentrations.Results The inhibition zones diameters of the pomegranate peel extracts against most common isolated bacteria (Staphylococcus aureus andEscherichia coli) increase significantly with increase in concentrations. There is no effect of the extracts on the ability of studied bacteria toproduce hemolysin and protease enzymes, while both studied bacteria lost its ability to produce β-lactamase enzyme after treating with MIC.In addition, extracts were affected largely on adherence activity and biofilm forming ability of tested bacteria. The results found that thepomegranate peel extracts effect alone against pathogenic bacteria was good than they interacted with antibiotics, in most of the results.Conclusion The alcohol extract was the best solvent in its effects on bacterial pathogen and its effect was largely on the ability of the studiedbacteria to form biofilm and adhesion on the epithelial cell. The pomegranate peel extracts were high synergism with some antibioticsagainst pathogenic bacteria.

scholarly journals Citrobacter rodentium, the Causative Agent of Transmissible Murine Colonic Hyperplasia, Exhibits Clonality: Synonymy of C. rodentium and Mouse-PathogenicEscherichia coli

2000 ◽  
Vol 38 (12) ◽  
pp. 4343-4350 ◽  
Author(s):  
Steven A. Luperchio ◽  
Joseph V. Newman ◽  
Charles A. Dangler ◽  
Mark D. Schrenzel ◽  
Don J. Brenner ◽  
...  
Keyword(s):  
Virulence Factors ◽  
Biochemical Characterization ◽  
Bacterial Pathogen ◽  
Pcr Analysis ◽  
Citrobacter Rodentium ◽  
Human Pathogens ◽  
E Coli ◽  
Hybridization Data ◽  
Enterocyte Effacement ◽  
Element Sequence

Citrobacter rodentium (formerly Citrobacter freundii biotype 4280 and Citrobacter genomospecies 9) was described on the basis of biochemical characterization and DNA-DNA hybridization data and is the only Citrobacterspecies known to possess virulence factors homologous to those of the human pathogens enteropathogenic Escherichia coli and enterohemorrhagic E. coli. These virulence factors are encoded on the locus of enterocyte effacement (LEE), a pathogenicity island required for the characteristic attaching and effacing (AE) pathology seen in infection with these three pathogens. C. rodentium, which apparently infects only mice, provides a useful animal model for studying the molecular basis of AE pathology. No work has been done to assess differences in pathogenicity between C. rodentium isolates from diverse sources. Here, we report the examination of 15 C. rodentium isolates using a battery of genetic and biochemical approaches. No differences were observed between the isolates by repetitive-element sequence-based PCR analysis, biochemical analysis, and possession of LEE-specific virulence factors. These data suggest that members of the species are clonal. We further characterized an atypical E. coli strain from Japan called mouse-pathogenic E. coli (MPEC) that, in our hands, caused the same disease as C. rodentium. Applying the same battery of tests, we found that MPEC possesses LEE-encoded virulence factors and is indistinguishable from the previously characterized C. rodentium isolate DBS100. These results demonstrate that MPEC is a misclassified C. rodentium isolate and that members of this species are clonal and represent the only known attaching and effacing bacterial pathogen of mice.

scholarly journals Antivirulence Strategies for the Treatment of Staphylococcus aureus Infections: A Mini Review

2021 ◽  
Vol 11 ◽  
Author(s):  
Caleb A. Ford ◽  
Ian M. Hurford ◽  
James E. Cassat
Keyword(s):  
Staphylococcus Aureus ◽  
Virulence Factors ◽  
Tissue Injury ◽  
Therapeutic Targets ◽  
Multiple Infection ◽  
Human Pathogens ◽  
Host Immune Responses ◽  
Infection Models ◽  
Antimicrobial Treatments

Staphylococcus aureus is a Gram-positive bacterium capable of infecting nearly all host tissues, causing severe morbidity and mortality. Widespread antimicrobial resistance has emerged among S. aureus clinical isolates, which are now the most frequent causes of nosocomial infection among drug-resistant pathogens. S. aureus produces an array of virulence factors that enhance in vivo fitness by liberating nutrients from the host or evading host immune responses. Staphylococcal virulence factors have been identified as viable therapeutic targets for treatment, as they contribute to disease pathogenesis, tissue injury, and treatment failure. Antivirulence strategies, or treatments targeting virulence without direct toxicity to the inciting pathogen, show promise as an adjunctive therapy to traditional antimicrobials. This Mini Review examines recent research on S. aureus antivirulence strategies, with an emphasis on translational studies. While many different virulence factors have been investigated as therapeutic targets, this review focuses on strategies targeting three virulence categories: pore-forming toxins, immune evasion mechanisms, and the S. aureus quorum sensing system. These major areas of S. aureus antivirulence research demonstrate broad principles that may apply to other human pathogens. Finally, challenges of antivirulence research are outlined including the potential for resistance, the need to investigate multiple infection models, and the importance of studying antivirulence in conjunction with traditional antimicrobial treatments.

scholarly journals Requirement of a mip-Like Gene for Virulence in the Phytopathogenic Bacterium Xanthomonas campestris pv. campestris

2007 ◽  
Vol 20 (1) ◽  
pp. 21-30 ◽  
Author(s):  
Ning Zang ◽  
Dong-Jie Tang ◽  
Mei-Liang Wei ◽  
Yong-Qiang He ◽  
Baoshan Chen ◽  
...  
Keyword(s):  
Virulence Factors ◽  
Legionella Pneumophila ◽  
Xanthomonas Campestris ◽  
Bacterial Pathogen ◽  
Replication Capacity ◽  
Human Pathogens ◽  
Extracellular Proteases ◽  
Ppiase Activity ◽  
Phytopathogenic Bacterium ◽  
Xanthomonas Campestris Pv Campestris

Macrophage infectivity potentiators (Mips) are FKBP domain-containing proteins reported as virulence factors in several human pathogens, such as members of genera Legionella, Salmonella and Chlamydia. The putative peptidyl-prolyl cis-trans isomerase (PPIase) encoded by XC2699 of the plant bacterial pathogen Xanthomonas campestris pv. campestris 8004 exhibits a 49% similarity at the aminoacid level to the Mip protein of Legionella pneumophila. This mip-like gene, XC2699, was overexpressed in Es-cherichia coli and the purified (His)6-tagged Mip-like protein encoded by XC2699 exhibited a PPIase activity specifically inhibited by FK-506. A mutation in the mip-like gene XC2699 led to significant reductions in virulence and replication capacity in the host plant Chinese radish (Raphanus sativus L. var. radiculus Pers.). Furthermore, the production of exopolysaccharide and the activity of extracellular proteases, virulence factors X. campestris pv. campestris, were significantly decreased in the mip-like mutant. These results reveal that the mip-like gene is involved in the pathogenesis of X. campestris pv. campestris through an effect on the production of these virulence factors.

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