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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 |

REPOSITORIES: biostudies-literature

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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.

Project description:Staphylococcus aureus lipoteichoic acid (LTA) is composed of a linear 1,3-linked polyglycerolphosphate chain and is tethered to the bacterial membrane by a glycolipid (diglucosyl-diacylglycerol [Glc2-DAG]). Glc2-DAG is synthesized in the bacterial cytoplasm by YpfP, a processive enzyme that transfers glucose to diacylglycerol (DAG), using UDP-glucose as its substrate. Here we present evidence that the S. aureus alpha-phosphoglucomutase (PgcA) and UTP:alpha-glucose 1-phosphate uridyltransferase (GtaB) homologs are required for the synthesis of Glc2-DAG. LtaA (lipoteichoic acid protein A), a predicted membrane permease whose structural gene is located in an operon with ypfP, is not involved in Glc2-DAG synthesis but is required for synthesis of glycolipid-anchored LTA. Our data suggest a model in which LtaA facilitates the transport of Glc2-DAG from the inner (cytoplasmic) leaflet to the outer leaflet of the plasma membrane, delivering Glc2-DAG as a substrate for LTA synthesis, thereby generating glycolipid-anchored LTA. Glycolipid anchoring of LTA appears to play an important role during infection, as S. aureus variants lacking ltaA display defects in the pathogenesis of animal infections.

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Septal secretion of protein A in Staphylococcus aureus 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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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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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 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.

| S-EPMC9426618 | biostudies-literature

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

Project description: Not available

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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?%).

| S-EPMC7187357 | biostudies-literature

Ftsh Sensitizes Methicillin-Resistant <i>Staphylococcus aureus</i> to β-Lactam Antibiotics by Degrading YpfP, a Lipoteichoic Acid Synthesis Enzyme.

Project description:In the Gram-positive pathogen Staphylococcus aureus, FtsH, a membrane-bound metalloprotease, plays a critical role in bacterial virulence and stress resistance. This protease is also known to sensitize methicillin-resistant Staphylococcus aureus (MRSA) to β-lactam antibiotics; however, the molecular mechanism is not known. Here, by the analysis of FtsH substrate mutants, we found that FtsH sensitizes MRSA specifically to β-lactams by degrading YpfP, the enzyme synthesizing the anchor molecule for lipoteichoic acid (LTA). Both the overexpression of FtsH and the disruption of ypfP-sensitized MRSA to β-lactams were observed. The knockout mutation in ftsH and ypfP increased the thickness of the cell wall. The β-lactam sensitization coincided with the production of aberrantly large LTA molecules. The combination of three mutations in the rpoC, vraB, and SAUSA300_2133 genes blocked the β-lactam-sensitizing effect of FtsH. Murine infection with the ypfP mutant could be treated by oxacillin, a β-lactam antibiotic ineffective against MRSA; however, the effective concentration of oxacillin differed depending on the S. aureus strain. Our study demonstrated that the β-lactam sensitizing effect of FtsH is due to its digestion of YpfP. It also suggests that the larger LTA molecules are responsible for the β-lactam sensitization phenotype, and YpfP is a viable target for developing novel anti-MRSA drugs.

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Staphylococcus aureus Lipoteichoic Acid Damages the Skin Barrier through an IL-1-Mediated Pathway.

Project description:Staphylococcus aureus is a significant bacterial pathogen that may penetrate through the barrier into the epidermis and dermis of the skin. We hypothesized that the S. aureus cell wall product lipoteichoic acid (LTA) may contribute to the development of inflammation and skin barrier defects; however, the effects of LTA in vivo are not well understood. In this study, we examined the effects induced by intradermal S. aureus LTA. We found that keratinocytes in LTA-treated skin were highly proliferative, expressing 10-fold increased levels of Ki67. Furthermore, we observed that LTA caused damage to the skin barrier with substantial loss of filaggrin and loricrin expression. In addition, levels of the IL-1 family of inflammatory cytokines, as well as the neutrophil-attracting chemokines Cxcl1 and Cxcl2, were increased. Concomitantly, we observed significant numbers of neutrophils infiltrating into the epidermis. Finally, we determined that LTA-induced signals were mediated in part through IL-1, because an IL-1 receptor type 1 antagonist ameliorated the effects of LTA, blocking neutrophil recruitment and increasing the expression of skin barrier proteins. In summary, we show that S. aureus LTA alone is sufficient to promote keratinocyte proliferation, inhibit expression of epidermal barrier proteins, induce IL-1 signaling, and recruit cells involved in skin inflammation.

| S-EPMC6650368 | biostudies-literature

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