scholarly journals Surface Glycopolymers Are Crucial forIn VitroAnti-Wall Teichoic Acid IgG-Mediated Complement Activation and Opsonophagocytosis of Staphylococcus aureus

2015 ◽  
Vol 83 (11) ◽  
pp. 4247-4255 ◽  
Author(s):  
Jong-Ho Lee ◽  
Na-Hyang Kim ◽  
Volker Winstel ◽  
Kenji Kurokawa ◽  
Jesper Larsen ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Teichoic Acid ◽  
Complement C3 ◽  
Glycerol Phosphate ◽  
Glycosylation Pattern ◽  
Wall Teichoic Acid ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Capsule Production ◽  
Cell Envelopes

ABSTRACTThe cell envelopes of many Gram-positive bacteria contain wall teichoic acids (WTAs).Staphylococcus aureusWTAs are composed of ribitol phosphate (RboP) or glycerol phosphate (GroP) backbones substituted withd-alanine andN-acetyl-d-glucosamine (GlcNAc) orN-acetyl-d-galactosamine (GalNAc). Two WTA glycosyltransferases, TarM and TarS, are responsible for modifying the RboP WTA with α-GlcNAc and β-GlcNAc, respectively. We recently reported that purified human serum anti-WTA IgG specifically recognizes β-GlcNAc of the staphylococcal RboP WTA and then facilitates complement C3 deposition and opsonophagocytosis ofS. aureuslaboratory strains. This prompted us to examine whether anti-WTA IgG can induce C3 deposition on a diverse set of clinicalS. aureusisolates. To this end, we compared anti-WTA IgG-mediated C3 deposition and opsonophagocytosis abilities using 13 different staphylococcal strains. Of note, the majority ofS. aureusstrains tested was recognized by anti-WTA IgG, resulting in C3 deposition and opsonophagocytosis. A minority of strains was not recognized by anti-WTA IgG, which correlated with either extensive capsule production or an alteration in the WTA glycosylation pattern. Our results demonstrate that the presence of WTAs with TarS-mediated glycosylation with β-GlcNAc in clinically isolatedS. aureusstrains is an important factor for induction of anti-WTA IgG-mediated C3 deposition and opsonophagocytosis.

scholarly journals Biosynthesis of the Unique Wall Teichoic Acid of Staphylococcus aureus Lineage ST395

mBio ◽  
2014 ◽  
Vol 5 (2) ◽  
Author(s):  
Volker Winstel ◽  
Patricia Sanchez-Carballo ◽  
Otto Holst ◽  
Guoqing Xia ◽  
Andreas Peschel
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Gene Transfer ◽  
Horizontal Gene Transfer ◽  
Biosynthesis Pathway ◽  
Glycerol Phosphate ◽  
Coagulase Negative Staphylococci ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Wall Teichoic Acids

ABSTRACT The major clonal lineages of the human pathogen Staphylococcus aureus produce cell wall-anchored anionic poly-ribitol-phosphate (RboP) wall teichoic acids (WTA) substituted with d-Alanine and N-acetyl-d-glucosamine. The phylogenetically isolated S. aureus ST395 lineage has recently been found to produce a unique poly-glycerol-phosphate (GroP) WTA glycosylated with N-acetyl-d-galactosamine (GalNAc). ST395 clones bear putative WTA biosynthesis genes on a novel genetic element probably acquired from coagulase-negative staphylococci (CoNS). We elucidated the ST395 WTA biosynthesis pathway and identified three novel WTA biosynthetic genes, including those encoding an α-O-GalNAc transferase TagN, a nucleotide sugar epimerase TagV probably required for generation of the activated sugar donor substrate for TagN, and an unusually short GroP WTA polymerase TagF. By using a panel of mutants derived from ST395, the GalNAc residues carried by GroP WTA were found to be required for infection by the ST395-specific bacteriophage Φ187 and to play a crucial role in horizontal gene transfer of S. aureus pathogenicity islands (SaPIs). Notably, ectopic expression of ST395 WTA biosynthesis genes rendered normal S. aureus susceptible to Φ187 and enabled Φ187-mediated SaPI transfer from ST395 to regular S. aureus. We provide evidence that exchange of WTA genes and their combination in variable, mosaic-like gene clusters have shaped the evolution of staphylococci and their capacities to undergo horizontal gene transfer events. IMPORTANCE The structural highly diverse wall teichoic acids (WTA) are cell wall-anchored glycopolymers produced by most Gram-positive bacteria. While most of the dominant Staphylococcus aureus lineages produce poly-ribitol-phosphate WTA, the recently described ST395 lineage produces a distinct poly-glycerol-phosphate WTA type resembling the WTA backbone of coagulase-negative staphylococci (CoNS). Here, we analyzed the ST395 WTA biosynthesis pathway and found new types of WTA biosynthesis genes along with an evolutionary link between ST395 and CoNS, from which the ST395 WTA genes probably originate. The elucidation of ST395 WTA biosynthesis will help to understand how Gram-positive bacteria produce highly variable WTA types and elucidate functional consequences of WTA variation.

scholarly journals Wall Teichoic Acid Glycosylation Governs Staphylococcus aureus Nasal Colonization

mBio ◽  
2015 ◽  
Vol 6 (4) ◽  
Author(s):  
Volker Winstel ◽  
Petra Kühner ◽  
Ferdinand Salomon ◽  
Jesper Larsen ◽  
Robert Skov ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Risk Factor ◽  
Epithelial Cells ◽  
Teichoic Acid ◽  
Nasal Colonization ◽  
Human Pathogen ◽  
Wall Teichoic Acid ◽  
Content Type ◽  
Human Nasal Epithelial Cells ◽  
Key Factor

ABSTRACT Nasal colonization by the human pathogen Staphylococcus aureus is a major risk factor for hospital- and community-acquired infections. A key factor required for nasal colonization is a cell surface-exposed zwitterionic glycopolymer, termed wall teichoic acid (WTA). However, the precise mechanisms that govern WTA-mediated nasal colonization have remained elusive. Here, we report that WTA GlcNAcylation is a pivotal requirement for WTA-dependent attachment of community-acquired methicillin-resistant S. aureus (MRSA) and emerging livestock-associated MRSA to human nasal epithelial cells, even under conditions simulating the nutrient composition and dynamic flow of nasal secretions. Depending on the S. aureus strain, WTA O-GlcNAcylation occurs in either α or β configuration, which have similar capacities to mediate attachment to human nasal epithelial cells, suggesting that many S. aureus strains maintain redundant pathways to ensure appropriate WTA glycosylation. Strikingly, a lack of WTA glycosylation significantly abrogated the ability of MRSA to colonize cotton rat nares in vivo. These results indicate that WTA glycosylation modulates S. aureus nasal colonization and may help to develop new strategies for eradicating S. aureus nasal colonization in the future. IMPORTANCE Nasal colonization by the major human pathogen Staphylococcus aureus is a risk factor for severe endogenous infections and contributes to the spread of this microbe in hospitals and the community. Here, we show that wall teichoic acid (WTA) O-GlcNAcylation is a key factor required for S. aureus nasal colonization. These data provide a mechanistic explanation for the capacity of WTA to modulate S. aureus nasal colonization and may stimulate research activities to establish valuable strategies to eradicate S. aureus nasal colonization in high-risk hospitalized patients and in the general community.

scholarly journals Wall Teichoic Acid Protects Staphylococcus aureus against Antimicrobial Fatty Acids from Human Skin

2009 ◽  
Vol 191 (13) ◽  
pp. 4482-4484 ◽  
Author(s):  
Thomas Kohler ◽  
Christopher Weidenmaier ◽  
Andreas Peschel
Keyword(s):  
Fatty Acids ◽  
Staphylococcus Aureus ◽  
Fatty Acid ◽  
Teichoic Acid ◽  
Sebaceous Glands ◽  
Wall Teichoic Acid ◽  
Fatty Acid Binding ◽  
Gram Positive Bacteria ◽  
Skin Colonization ◽  
Wall Teichoic Acids

ABSTRACT Skin-colonizing gram-positive bacteria produce wall teichoic acids (WTAs) or related glycopolymers for unclear reasons. Using a WTA-deficient Staphylococcus aureus mutant, we demonstrated that WTA confers resistance to antimicrobial fatty acids from human sebaceous glands by preventing fatty acid binding. Thus, WTA is probably important for bacterial skin colonization.

scholarly journals Studies on the linkage between teichoic acid and peptidoglycan in a bacteriophage-resistant mutant of Staphylococcus aureus H

1975 ◽  
Vol 149 (3) ◽  
pp. 637-647 ◽  
Author(s):  
J E Heckels ◽  
A R Archibald ◽  
J Baddiley
Keyword(s):  
Staphylococcus Aureus ◽  
Teichoic Acid ◽  
Resistant Mutant ◽  
Muramic Acid ◽  
Glycerol Phosphate ◽  
Wall Teichoic Acid ◽  
Phosphodiester Linkage ◽  
A Chain

1. In addition to poly(ribitol phosphate) the walls of a bacteriophage-resistant mutant of Staphylococcus aureus H contain glycerol phosphate residues that are not removed on digestion with trypsin or extraction with phenol. 2. The glycerol phosphate is present in a chain, containing three or four glycerol phosphate residues, which is covalently attached to the peptidoglycan through a phosphodiester linkage to muramic acid; this linkage is readily hydrolysed by dilute alkali. 3. The degradative studies described suggest that the poly(ribitol phosphate) chains of the wall teichoic acid may be attached to the wall by linkage to this glycerol phosphate oligomer.

scholarly journals Structure and Mechanism of LcpA, a Phosphotransferase That Mediates Glycosylation of a Gram-Positive Bacterial Cell Wall-Anchored Protein

mBio ◽  
2019 ◽  
Vol 10 (1) ◽  
Author(s):  
Sara D. Siegel ◽  
Brendan R. Amer ◽  
Chenggang Wu ◽  
Michael R. Sawaya ◽  
Jason E. Gosschalk ◽  
...  
Keyword(s):  
Cell Wall ◽  
Disulfide Bond ◽  
Cell Envelope ◽  
Teichoic Acid ◽  
Surface Proteins ◽  
Wall Teichoic Acid ◽  
Gram Positive ◽  
Content Type ◽  
X Ray Crystallography ◽  
Gram Positive Bacteria

ABSTRACT The widely conserved LytR-CpsA-Psr (LCP) family of enzymes in Gram-positive bacteria is known to attach glycopolymers, including wall teichoic acid, to the cell envelope. However, it is undetermined if these enzymes are capable of catalyzing glycan attachment to surface proteins. In the actinobacterium Actinomyces oris, an LCP homolog here named LcpA is genetically linked to GspA, a glycoprotein that is covalently attached to the bacterial peptidoglycan by the housekeeping sortase SrtA. Here we show by X-ray crystallography that LcpA adopts an α-β-α structural fold, akin to the conserved LCP domain, which harbors characteristic catalytic arginine residues. Consistently, alanine substitution for these residues, R149 and R266, abrogates GspA glycosylation, leading to accumulation of an intermediate form termed GspALMM, which is also observed in the lcpA mutant. Unlike other LCP proteins characterized to date, LcpA contains a stabilizing disulfide bond, mutations of which severely affect LcpA stability. In line with the established role of disulfide bond formation in oxidative protein folding in A. oris, deletion of vkor, coding for the thiol-disulfide oxidoreductase VKOR, also significantly reduces LcpA stability. Biochemical studies demonstrated that the recombinant LcpA enzyme possesses pyrophosphatase activity, enabling hydrolysis of diphosphate bonds. Furthermore, this recombinant enzyme, which weakly interacts with GspA in solution, catalyzes phosphotransfer to GspALMM. Altogether, the findings support that A. oris LcpA is an archetypal LCP enzyme that glycosylates a cell wall-anchored protein, a process that may be conserved in Actinobacteria, given the conservation of LcpA and GspA in these high-GC-content organisms. IMPORTANCE In Gram-positive bacteria, the conserved LCP family enzymes studied to date are known to attach glycopolymers, including wall teichoic acid, to the cell envelope. It is unknown if these enzymes catalyze glycosylation of surface proteins. We show here in the actinobacterium Actinomyces oris by X-ray crystallography and biochemical analyses that A. oris LcpA is an LCP homolog, possessing pyrophosphatase and phosphotransferase activities known to belong to LCP enzymes that require conserved catalytic Arg residues, while harboring a unique disulfide bond critical for protein stability. Importantly, LcpA mediates glycosylation of the surface protein GspA via phosphotransferase activity. Our studies provide the first experimental evidence of an archetypal LCP enzyme that promotes glycosylation of a cell wall-anchored protein in Gram-positive bacteria.

scholarly journals Langerhans Cells SenseStaphylococcus aureusWall Teichoic Acid through Langerin To Induce Inflammatory Responses

mBio ◽  
2019 ◽  
Vol 10 (3) ◽  
Author(s):  
Rob van Dalen ◽  
Jacinto S. De La Cruz Diaz ◽  
Matevž Rumpret ◽  
Felix F. Fuchsberger ◽  
Nienke H. van Teijlingen ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Langerhans Cells ◽  
Molecular Mechanisms ◽  
Inflammatory Responses ◽  
Teichoic Acid ◽  
Infection Model ◽  
Wall Teichoic Acid ◽  
Content Type ◽  
Staphylococcal Species ◽  
Specific Subset

ABSTRACTStaphylococcus aureusis a major cause of skin and soft tissue infections and aggravator of the inflammatory skin disease atopic dermatitis (AD [eczema]). Epicutaneous exposure toS. aureusinduces Th17 responses through skin Langerhans cells (LCs), which paradoxically contribute to host defense but also to AD pathogenesis. The molecular mechanisms underlying the interaction betweenS. aureusand LCs are poorly understood. Here we demonstrate that human LCs directly interact withS. aureusthrough the pattern recognition receptor langerin (CD207). Human, but not mouse, langerin interacts withS. aureusthrough the conserved β-N-acetylglucosamine (GlcNAc) modifications on wall teichoic acid (WTA), thereby discriminatingS. aureusfrom other staphylococcal species. Importantly, the specificS. aureusWTA glycoprofile strongly influences the level of proinflammatory cytokines that are produced byin vitro-generated LCs. Finally, in a murine epicutaneous infection model,S. aureusstrongly upregulated transcripts ofCxcl1,Il6, andIl17, which required the presence of both human langerin and WTA β-GlcNAc. Our findings provide molecular insight into the unique proinflammatory capacities ofS. aureusin relation to skin inflammation.IMPORTANCEThe bacteriumStaphylococcus aureusis an important cause of skin infections and is also associated with the occurrence and severity of eczema. Langerhans cells (LCs), a specific subset of skin immune cells, participate in the immune response toS. aureus, but it is yet unclear how LCs recognizeS. aureus. Therefore, we investigated the molecular mechanism underlying the interaction between LCs andS. aureus. We identified that wall teichoic acid, an abundant polymer on theS. aureussurface, is recognized by langerin, a receptor unique to LCs. This interaction allows LCs to discriminateS. aureusfrom other related staphylococcal species and initiates a proinflammatory response similar to that observed in patients with eczema. Our data therefore provide important new insights into the relationship betweenS. aureus, LCs, and eczema.

scholarly journals Unprotonated Short-Chain Alkylamines Inhibit Staphylolytic Activity of Lysostaphin in a Wall Teichoic Acid-Dependent Manner

2018 ◽  
Vol 84 (14) ◽  
Author(s):  
Xia Wu ◽  
Seok Joon Kwon ◽  
Domyoung Kim ◽  
Jian Zha ◽  
Mauricio Mora-Pale ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Respiratory Infections ◽  
Teichoic Acid ◽  
Inhibitory Effect ◽  
Short Chain ◽  
Dependent Manner ◽  
Cell Binding ◽  
Wall Teichoic Acid ◽  
Content Type ◽  
The Impact

ABSTRACTLysostaphin (Lst) is a potent bacteriolytic enzyme that killsStaphylococcus aureus, a common bacterial pathogen of humans and animals. With high activity against both planktonic cells and biofilms, Lst has the potential to be used in industrial products, such as commercial cleansers, for decontamination. However, Lst is inhibited in the presence of monoethanolamine (MEA), a chemical widely used in cleaning solutions and pharmaceuticals, and the underlying mechanism of inhibition remains unknown. In this study, we examined the cell binding and killing capabilities of Lst againstS. aureusATCC 6538 in buffered salt solution with MEA at different pH values (7.5 to 10.5) and discovered that only the unprotonated form of MEA inhibited Lst binding to the cell surface, leading to low Lst activity, despite retention of its secondary structure. This reduced enzyme activity could be largely recovered via a reduction in wall teichoic acid (WTA) biosynthesis through tunicamycin treatment, indicating that the suppression of Lst activity was dependent on the presence and amount of WTA. We propose that the decreased cell binding and killing capabilities of Lst are associated with the influence of uncharged MEA on the conformation of WTA. A similar effect was confirmed with other short-chain alkylamines. This study offers new insight into the impact of short-chain alkylamines on both Lst and WTA structure and function and provides guidance for the application of Lst in harsh environments.IMPORTANCELysostaphin (Lst) effectively and selectively killsStaphylococcus aureus, the bacterial culprit of many hospital- and community-acquired skin and respiratory infections and food poisoning. Lst has been investigated in animal models and clinical trials, industrial formulations, and environmental settings. Here, we studied the mechanistic basis of the inhibitory effect of alkylamines, such as monoethanolamine (MEA), a widely used chemical in commercial detergents, on Lst activity, for the potential incorporation of Lst in disinfectant solutions. We have found that protonated MEA has little influence on Lst activity, while unprotonated MEA prevents Lst from binding toS. aureuscells and hence dramatically decreases the enzyme's bacteriolytic efficacy. Following partial removal of the wall teichoic acid, an important component of the bacterial cell envelope, the inhibitory effect of unprotonated MEA on Lst is reduced. This phenomenon can be extended to other short-chain alkylamines. This mechanistic report of the impact of alkylamines on Lst functionality will help guide future applications of Lst in disinfection and decontamination of health-related commercial products.

scholarly journals An Antibiotic That Inhibits a Late Step in Wall Teichoic Acid Biosynthesis Induces the Cell Wall Stress Stimulon in Staphylococcus aureus

2012 ◽  
Vol 56 (4) ◽  
pp. 1810-1820 ◽  
Author(s):  
Jennifer Campbell ◽  
Atul K. Singh ◽  
Jonathan G. Swoboda ◽  
Michael S. Gilmore ◽  
Brian J. Wilkinson ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Cell Wall ◽  
Osmotic Stress ◽  
Late Stage ◽  
Teichoic Acid ◽  
Wall Stress ◽  
Wall Teichoic Acid ◽  
Content Type ◽  
Cell Wall Stress

ABSTRACTWall teichoic acids (WTAs) are phosphate-rich, sugar-based polymers attached to the cell walls of most Gram-positive bacteria. InStaphylococcus aureus, these anionic polymers regulate cell division, protect cells from osmotic stress, mediate host colonization, and mask enzymatically susceptible peptidoglycan bonds. Although WTAs are not required for survivalin vitro, blocking the pathway at a late stage of synthesis is lethal. We recently discovered a novel antibiotic, targocil, that inhibits a late acting step in the WTA pathway. Its target is TarG, the transmembrane component of the ABC transporter (TarGH) that exports WTAs to the cell surface. We examined here the effects of targocil onS. aureususing transmission electron microscopy and gene expression profiling. We report that targocil treatment leads to multicellular clusters containing swollen cells displaying evidence of osmotic stress, strongly induces the cell wall stress stimulon, and reduces the expression of key virulence genes, includingdltABCDand capsule genes. We conclude that WTA inhibitors that act at a late stage of the biosynthetic pathway may be useful as antibiotics, and we present evidence that they could be particularly useful in combination with beta-lactams.

scholarly journals Staphylococcus aureus Metabolic Adaptations during the Transition from a Daptomycin Susceptibility Phenotype to a Daptomycin Nonsusceptibility Phenotype

2015 ◽  
Vol 59 (7) ◽  
pp. 4226-4238 ◽  
Author(s):  
Rosmarie Gaupp ◽  
Shulei Lei ◽  
Joseph M. Reed ◽  
Henrik Peisker ◽  
Susan Boyle-Vavra ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Tricarboxylic Acid Cycle ◽  
Teichoic Acid ◽  
Common Mechanism ◽  
Virulence Determinants ◽  
Wall Teichoic Acid ◽  
Content Type ◽  
Adaptive Resistance ◽  
Peptidoglycan Biosynthesis ◽  
Delayed Transition

ABSTRACTStaphylococcus aureusis a major cause of nosocomial and community-acquired infections. The success ofS. aureusas a pathogen is due in part to its many virulence determinants and resistance to antimicrobials. In particular, methicillin-resistantS. aureushas emerged as a major cause of infections and led to increased use of the antibiotics vancomycin and daptomycin, which has increased the isolation of vancomycin-intermediateS. aureusand daptomycin-nonsusceptibleS. aureusstrains. The most common mechanism by whichS. aureusacquires intermediate resistance to antibiotics is by adapting its physiology and metabolism to permit growth in the presence of these antibiotics, a process known as adaptive resistance. To better understand the physiological and metabolic changes associated with adaptive resistance, six daptomycin-susceptible and -nonsusceptible isogenic strain pairs were examined for changes in growth, competitive fitness, and metabolic alterations. Interestingly, daptomycin nonsusceptibility coincides with a slightly delayed transition to the postexponential growth phase and alterations in metabolism. Specifically, daptomycin-nonsusceptible strains have decreased tricarboxylic acid cycle activity, which correlates with increased synthesis of pyrimidines and purines and increased carbon flow to pathways associated with wall teichoic acid and peptidoglycan biosynthesis. Importantly, these data provided an opportunity to alter the daptomycin nonsusceptibility phenotype by manipulating bacterial metabolism, a first step in developing compounds that target metabolic pathways that can be used in combination with daptomycin to reduce treatment failures.

scholarly journals Metabolic Mitigation of Staphylococcus aureus Vancomycin Intermediate-Level Susceptibility

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Stewart G. Gardner ◽  
Darrell D. Marshall ◽  
Robert S. Daum ◽  
Robert Powers ◽  
Greg A. Somerville
Keyword(s):  
Staphylococcus Aureus ◽  
Teichoic Acid ◽  
Tca Cycle ◽  
Amino Sugar ◽  
Pentose Phosphate ◽  
Metabolic Changes ◽  
Purine Biosynthesis ◽  
Wall Teichoic Acid ◽  
Content Type ◽  
Adaptive Resistance

ABSTRACTStaphylococcus aureusis a major human pathogen whose infections are increasingly difficult to treat due to increased antibiotic resistance, including resistance to vancomycin. Vancomycin-intermediateS. aureus(VISA) strains develop resistance to vancomycin through adaptive changes that are incompletely understood. Central to this adaptation are metabolic changes that permit growth in the presence of vancomycin. To define the metabolic changes associated with adaptive resistance to vancomycin inS. aureus, the metabolomes of a vancomycin-sensitive and VISA strain pair isolated from the same patient shortly after vancomycin therapy began and following vancomycin treatment failure were analyzed. The metabolic adaptations included increases in acetogenesis, carbon flow through the pentose phosphate pathway, wall teichoic acid and peptidoglycan precursor biosynthesis, purine biosynthesis, and decreased tricarboxylic acid (TCA) cycle activity. The significance of these metabolic pathways for vancomycin-intermediate susceptibility was determined by assessing the synergistic potential of human-use-approved inhibitors of these pathways in combination with vancomycin against VISA strains. Importantly, inhibitors of amino sugar and purine biosynthesis acted synergistically with vancomycin to kill a diverse set of VISA strains, suggesting that combinatorial therapy could augment the efficacy of vancomycin even in patients infected with VISA strains.

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