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Synthesis of glycerol phosphate lipoteichoic acid in Staphylococcus aureus.

ABSTRACT: Lipoteichoic acid (LTA), a glycerol phosphate surface polymer, is a component of the envelope of Gram-positive bacteria. However, the molecular basis for its synthesis or function is not known. Here we report that Staphylococcus aureus LtaS synthesizes glycerol phosphate LTA. Construction of a mutant S. aureus strain with inducible ltaS expression revealed that LTA synthesis is required for bacterial growth and cell division. An ltaS homologue of Bacillus subtilis restored LTA synthesis and the growth of ltaS mutant staphylococci. Thus, LtaS inhibition can be used as a target to treat human infections caused by antibiotic-resistant S. aureus or other bacterial pathogens.

SUBMITTER: Grundling A

PROVIDER: S-EPMC1895975 | biostudies-literature | 2007 May

REPOSITORIES: biostudies-literature

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Synthesis of glycerol phosphate lipoteichoic acid in Staphylococcus aureus.

Gründling Angelika A Schneewind Olaf O

Proceedings of the National Academy of Sciences of the United States of America 20070503 20

Lipoteichoic acid (LTA), a glycerol phosphate surface polymer, is a component of the envelope of Gram-positive bacteria. However, the molecular basis for its synthesis or function is not known. Here we report that Staphylococcus aureus LtaS synthesizes glycerol phosphate LTA. Construction of a mutant S. aureus strain with inducible ltaS expression revealed that LTA synthesis is required for bacterial growth and cell division. An ltaS homologue of Bacillus subtilis restored LTA synthesis and the ...[more]

PMID: 17483484

Similar Datasets

Structure-based mechanism of lipoteichoic acid synthesis by Staphylococcus aureus LtaS.

Project description:Staphylococcus aureus synthesizes polyglycerol-phosphate lipoteichoic acid (LTA) from phosphatidylglycerol. LtaS, a predicted membrane protein with 5 N-terminal transmembrane helices followed by a large extracellular part (eLtaS), is required for staphylococcal growth and LTA synthesis. Here, we report the first crystal structure of the eLtaS domain at 1.2-A resolution and show that it assumes a sulfatase-like fold with an alpha/beta core and a C-terminal part composed of 4 anti-parallel beta-strands and a long alpha-helix. Overlaying eLtaS with sulfatase structures identified active site residues, which were confirmed by alanine substitution mutagenesis and in vivo enzyme function assays. The cocrystal structure with glycerol-phosphate and the coordination of a Mn(2+) cation allowed us to propose a reaction mechanism, whereby the active site threonine of LtaS functions as nucleophile for phosphatidylglycerol hydrolysis and formation of a covalent threonine-glycerolphosphate intermediate. These results will aid in the development of LtaS-specific inhibitors for S. aureus and many other Gram-positive pathogens.

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Genes required for glycolipid synthesis and lipoteichoic acid anchoring in Staphylococcus aureus.

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Proteolytic cleavage inactivates the Staphylococcus aureus lipoteichoic acid synthase.

Project description:Lipoteichoic acid (LTA) is a crucial cell envelope component in Gram-positive bacteria. In Staphylococcus aureus, the polyglycerolphosphate LTA molecule is synthesized by LtaS, a membrane-embedded enzyme with five N-terminal transmembrane helices (5TM domain) that are connected via a linker region to the C-terminal extracellular enzymatic domain (eLtaS). The LtaS enzyme is processed during bacterial growth, and the eLtaS domain is released from the bacterial membrane. Here we provide experimental evidence that the proteolytic cleavage following residues 215Ala-Leu-Ala217 is performed by the essential S. aureus signal peptidase SpsB, as depletion of spsB results in reduced LtaS processing. In addition, the introduction of a proline residue at the +1 position with respect to the cleavage site, a substitution known to inhibit signal peptidase-dependent cleavage, abolished LtaS processing at this site. It was further shown that the 5TM domain is crucial for enzyme function. The observation that the construction of hybrid proteins between two functional LtaS-type enzymes resulted in the production of proteins unable to synthesize LTA suggests that specific interactions between the 5TM and eLtaS domains are required for function. No enzyme activity was detected upon expression of the 5TM and eLtaS domains as separate fragments, indicating that the two domains cannot assemble postsynthesis to form a functional enzyme. Taken together, our data suggest that only the full-length LtaS enzyme is active in the LTA synthesis pathway and that the proteolytic cleavage step is used as a mechanism to irreversibly inactivate the enzyme.

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Septal secretion of protein A in <i>Staphylococcus aureus</i> requires SecA and lipoteichoic acid synthesis.

Project description:Surface proteins of Staphylococcus aureus are secreted across septal membranes for assembly into the bacterial cross-wall. This localized secretion requires the YSIRK/GXXS motif signal peptide, however the mechanisms supporting precursor trafficking are not known. We show here that the signal peptide of staphylococcal protein A (SpA) is cleaved at the YSIRK/GXXS motif. A SpA signal peptide mutant defective for YSIRK/GXXS cleavage is also impaired for septal secretion and co-purifies with SecA, SecDF and LtaS. SecA depletion blocks precursor targeting to septal membranes, whereas deletion of secDF diminishes SpA secretion into the cross-wall. Depletion of LtaS blocks lipoteichoic acid synthesis and abolishes SpA precursor trafficking to septal membranes. We propose a model whereby SecA directs SpA precursors to lipoteichoic acid-rich septal membranes for YSIRK/GXXS motif cleavage and secretion into the cross-wall.

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Staphylococcus aureus Lipoteichoic Acid Inhibits Keratinocyte Differentiation through a p63-Mediated Pathway.

Project description: Not available

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Staphylococcus aureus lipoteichoic acid-stimulated undifferentiated and neutrophil-like differentiated HL-60 cells

Project description:HL-60 is a human promyelocytic leukemia cell line and differentiated HL-60 is an alternative to human primary neutrophils. The transcriptomic profile of undifferentiated HL-60 and dimethyl sulfoxide-differentiated HL-60 were determined at 4 and 24 hours after stimulation with high and low concentrations of Staphylococcus aureus lipoteichoic acids.

2023-12-15 | GSE239859 | GEO

Staphylococcus aureus Lipoteichoic Acid Initiates a TSLP-Basophil-IL4 Axis in the Skin.

Project description: Not available

| S-EPMC7075722 | biostudies-literature

Staphylococcus aureus controls eicosanoid and specialized pro-resolving mediator production via lipoteichoic acid.

Project description:Staphylococcus aureus causes severe infections associated with inflammation, such as sepsis or osteomyelitis. Inflammatory processes are regulated by distinct lipid mediators (LMs) but how their biosynthetic pathways are orchestrated in S. aureus infections is elusive. We show that S. aureus strikingly not only modulates pro-inflammatory, but also inflammation-resolving LM pathways in murine osteomyelitis and osteoclasts as well as in human monocyte-derived macrophages (MDMs) with different phenotype. Targeted LM metabololipidomics using ultra-performance liquid chromatography-tandem mass spectrometry revealed massive generation of LM with distinct LM signature profiles in acute and chronic phases of S. aureus-induced murine osteomyelitis in vivo. In human MDM, S. aureus elevated cyclooxygenase-2 (COX-2) and microsomal prostaglandin E2 synthase-1 (mPGES-1), but impaired the levels of 15-lipoxygenase-1 (15-LOX-1), with respective changes in LM signature profiles initiated by these enzymes, that is, elevated PGE2 and impaired specialized pro-resolving mediators, along with reduced M2-like phenotypic macrophage markers. The cell wall component, lipoteichoic acid (LTA), mimicked the impact of S. aureus elevating COX-2/mPGES-1 expression via NF-κB and p38 MAPK signalling in MDM, while the impairment of 15-LOX-1 correlates with reduced expression of Lamtor1. In conclusion, S. aureus dictates LM pathways via LTA resulting in a shift from anti-inflammatory M2-like towards pro-inflammatory M1-like LM signature profiles.

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Preconditioning with Lipopolysaccharide or Lipoteichoic Acid Protects against Staphylococcus aureus Mammary Infection in Mice.

Project description:Staphylococcus aureus is one of the most causative agents of mastitis and is associated with chronic udder infections. The persistency of the pathogen is believed to be the result of an insufficient triggering of local inflammatory signaling. In this study, the preclinical mastitis model was used, aiming to evaluate if lipopolysaccharide (LPS) or lipoteichoic acid (LTA) preconditioning could aid the host in more effectively clearing or at least limiting a subsequent S. aureus infection. A prototypic Gram-negative virulence factor, i.e., LPS and Gram-positive virulence factor, i.e., LTA were screened whether they were able to boost the local immune compartment. Compared to S. aureus-induced inflammation, both toxins had a remarkable high potency to efficiently induce two novel selected innate immunity biomarkers i.e., lipocalin 2 (LCN2) and chitinase 3-like 1 (CHI3L1). When combining mammary inoculation of LPS or LTA prior to a local S. aureus infection, we were able to modulate the innate immune response, reduce local bacterial loads, and induce either LCN2 or CHI3L1 at 24 h post-infection. Clodronate depletion of mammary macrophages also identified that macrophages contribute only to a limited extend to the LPS/LTA-induced immunomodulation upon S. aureus infection. Based on histological neutrophil influx evaluation, concomitant local cytokine profiles and LCN2/CHI3L1 patterns, the macrophage-independent signaling plays a major role in the LPS- or LTA-pretreated S. aureus-infected mouse mammary gland. Our results highlight the importance of a vigilant microenvironment during the innate immune response of the mammary gland and offer novel insights for new approaches concerning effective immunomodulation against a local bacterial infection.

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Preparative-Scale Enzymatic Synthesis of rac-Glycerol-1-phosphate from Crude Glycerol Using Acid Phosphatases and Phosphate.

Project description:Glycerol is a byproduct of biodiesel production and is generated in large amounts, which has resulted in an increased interest in its valorization. In addition to its use as an energy source directly, the chemical modification of glycerol may result in value-added derivatives. Herein, acid phosphatases employed in the synthetic mode were evaluated for the enzymatic phosphorylation of glycerol. Nonspecific acid phosphatases could tolerate glycerol concentrations up to 80 wt % and pyrophosphate concentrations up to 20 wt % and led to product titers up to 167 g L-1 in a kinetic approach. In the complementary thermodynamic approach, phytases were able to condense glycerol and inorganic monophosphate directly. This unexpected behavior enabled the simple and cost-effective production of rac-glycerol-1-phosphate from crude glycerol obtained from a biodiesel plant. A preparative-scale synthesis on a 100 mL-scale resulted in the production of 16.6 g of rac-glycerol-1-phosphate with a reasonable purity (≈75 %).

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