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Olaf Schneewind - One of the best experts on this subject based on the ideXlab platform.
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septal secretion of protein a in staphylococcus aureus requires seca and Lipoteichoic Acid synthesis
eLife, 2018Co-Authors: Dominique Missiakas, Olaf SchneewindAbstract: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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septal secretion of protein a in staphylococcus aureus requires seca and Lipoteichoic Acid synthesis
bioRxiv, 2018Co-Authors: Dominique Missiakas, Olaf SchneewindAbstract: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 signal peptide mutant defective for cleavage can be crosslinked to 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 promotes precursor trafficking to peripheral 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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synthesis of glycerol phosphate Lipoteichoic Acid in staphylococcus aureus
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Angelika Grundling, Olaf SchneewindAbstract: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.
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genes required for glycolipid synthesis and Lipoteichoic Acid anchoring in staphylococcus aureus
Journal of Bacteriology, 2007Co-Authors: Angelika Grundling, Olaf SchneewindAbstract: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 α-phosphoglucomutase (PgcA) and UTP:α-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.
Angelika Grundling - One of the best experts on this subject based on the ideXlab platform.
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the cell wall polymer Lipoteichoic Acid becomes nonessential in staphylococcus aureus cells lacking the clpx chaperone
Mbio, 2016Co-Authors: Kristoffer T Baek, Lisa Bowman, Charlotte Millership, Mia Dupont Sogaard, Volkhard Kaever, Pia Siljamaki, Kirsi Savijoki, Pekka Varmanen, Tuula A Nyman, Angelika GrundlingAbstract:ABSTRACT Lipoteichoic Acid (LTA) is an important cell wall component of Gram-positive bacteria and a promising target for the development of vaccines and antimicrobial compounds against Staphylococcus aureus. Here we demonstrate that mutations in the conditionally essential ltaS (LTA synthase) gene arise spontaneously in an S. aureus mutant lacking the ClpX chaperone. A wide variety of ltaS mutations were selected, and among these, a substantial portion resulted in premature stop codons and other changes predicted to abolish LtaS synthesis. Consistent with this assumption, the clpX ltaS double mutants did not produce LTA, and genetic analyses confirmed that LTA becomes nonessential in the absence of the ClpX chaperone. In fact, inactivation of ltaS alleviated the severe growth defect conferred by the clpX deletion. Microscopic analyses showed that the absence of ClpX partly alleviates the septum placement defects of an LTA-depleted strain, while other phenotypes typical of LTA-negative S. aureus mutants, including increased cell size and decreased autolytic activity, are retained. In conclusion, our results indicate that LTA has an essential role in septum placement that can be bypassed by inactivating the ClpX chaperone. IMPORTANCE Lipoteichoic Acid is an essential component of the Staphylococcus aureus cell envelope and an attractive target for the development of vaccines and antimicrobials directed against antibiotic-resistant Gram-positive bacteria such as methicillin-resistant S. aureus and vancomycin-resistant enterococci. In this study, we showed that the Lipoteichoic Acid polymer is essential for growth of S. aureus only as long as the ClpX chaperone is present in the cell. Our results indicate that Lipoteichoic Acid and ClpX play opposite roles in a pathway that controls two key cell division processes in S. aureus, namely, septum formation and autolytic activity. The discovery of a novel functional connection in the genetic network that controls cell division in S. aureus may expand the repertoire of possible strategies to identify compounds or compound combinations that kill antibiotic-resistant S. aureus.
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Lipoteichoic Acid synthesis and function in gram positive bacteria
Annual Review of Microbiology, 2014Co-Authors: Matthew G Percy, Angelika GrundlingAbstract:Lipoteichoic Acid (LTA) is an important cell wall polymer found in grampositive bacteria. Although the exact role of LTA is unknown, mutants display significant growth and physiological defects. Additionally, modification of the LTA backbone structure can provide protection against cationic antimicrobial peptides. This review provides an overview of the different LTA types and their chemical structures and synthesis pathways. The occurrence and mechanisms of LTA modifications with D-alanyl, glycosyl, and phosphocholine residues will be discussed along with their functions. Similarities between the production of type I LTA and osmoregulated periplasmic glucans in gram-negative bacteria are highlighted, indicating that LTA should perhaps be compared to these polymers rather than lipopolysaccharide, as is presently the case. Lastly, current efforts to use LTAs as vaccine candidates, synthesis proteins as novel antimicrobial targets, and LTA mutant strains as improved probiotics are highlighted.
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in vitro analysis of the staphylococcus aureus Lipoteichoic Acid synthase enzyme using fluorescently labeled lipids
Journal of Bacteriology, 2010Co-Authors: Maria Karatsadodgson, Mirka E Wormann, Angelika GrundlingAbstract:Lipoteichoic Acid (LTA) is an important cell wall component of Gram-positive bacteria. The key enzyme responsible for polyglycerolphosphate Lipoteichoic Acid synthesis in the Gram-positive pathogen Staphylococcus aureus is the membrane-embedded Lipoteichoic Acid synthase enzyme, LtaS. It is presumed that LtaS hydrolyzes the glycerolphosphate head group of the membrane lipid phosphatidylglycerol (PG) and catalyzes the formation of the polyglycerolphosphate LTA backbone chain. Here we describe an in vitro assay for this new class of enzyme using PG with a fluorescently labeled fatty Acid chain (NBD-PG) as the substrate and the recombinant soluble C-terminal enzymatic domain of LtaS (eLtaS). Thin-layer chromatography and mass spectrometry analysis of the lipid reaction products revealed that eLtaS is sufficient to cleave the glycerolphosphate head group from NBD-PG, resulting in the formation of NBD-diacylglycerol. An excess of soluble glycerolphosphate could not compete with the hydrolysis of the fluorescently labeled PG lipid substrate, in contrast to the addition of unlabeled PG. This indicates that the enzyme recognizes and binds other parts of the lipid substrate, besides the glycerolphosphate head group. Furthermore, eLtaS activity was Mn2+ ion dependent; Mg2+ and Ca2+ supported only weak enzyme activity. Addition of Zn2+ or EDTA inhibited enzyme activity even in the presence of Mn2+. The pH optimum of the enzyme was 6.5, characteristic for an enzyme that functions extracellularly. Lastly, we show that the in vitro assay can be used to study the enzyme activities of other members of the Lipoteichoic Acid synthase enzyme family.
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synthesis of glycerol phosphate Lipoteichoic Acid in staphylococcus aureus
Proceedings of the National Academy of Sciences of the United States of America, 2007Co-Authors: Angelika Grundling, Olaf SchneewindAbstract: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.
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genes required for glycolipid synthesis and Lipoteichoic Acid anchoring in staphylococcus aureus
Journal of Bacteriology, 2007Co-Authors: Angelika Grundling, Olaf SchneewindAbstract: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 α-phosphoglucomutase (PgcA) and UTP:α-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.
Christoph Thiemermann - One of the best experts on this subject based on the ideXlab platform.
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peptidoglycan and Lipoteichoic Acid in gram positive bacterial sepsis receptors signal transduction biological effects and synergism
Shock, 2003Co-Authors: Jacob E Wang, Maria K Dahle, Michelle C Mcdonald, Simon J Foster, A O Aasen, Christoph ThiemermannAbstract:In sepsis and multiple organ dysfunction syndrome (MODS) caused by gram-negative bacteria, lipopoly- saccharide (LPS) initiates the early signaling events leading to the deleterious inflammatory response. However, it has become clear that LPS can not reproduce all of the clinical features of sepsis, which emphasize the roles of other contributing factors. Gram-positive bacteria, which lack LPS, are today responsible for a substantial part of the incidents of sepsis with MODS. The major wall components of gram-positive bacteria, peptidoglycan and Lipoteichoic Acid, are thought to contribute to the development of sepsis and MODS. In this review, the literature underlying our current understanding of how peptidoglycan and Lipoteichoic Acid activate inflammatory responses will be presented, with a focus on recent advances in this field. KEYWORDS—Gram-positive bacteria, sepsis, MODS, cytokines, peptidoglycan, Lipoteichoic Acid
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peptidoglycan and Lipoteichoic Acid in gram positive bacterial sepsis receptors signal transduction biological effects and synergism
Shock, 2003Co-Authors: Jacob E Wang, Maria K Dahle, Michelle C Mcdonald, Simon J Foster, A O Aasen, Christoph ThiemermannAbstract:In sepsis and multiple organ dysfunction syndrome (MODS) caused by gram-negative bacteria, lipopolysaccharide (LPS) initiates the early signaling events leading to the deleterious inflammatory response. However, it has become clear that LPS can not reproduce all of the clinical features of sepsis, which emphasize the roles of other contributing factors. Gram-positive bacteria, which lack LPS, are today responsible for a substantial part of the incidents of sepsis with MODS. The major wall components of gram-positive bacteria, peptidoglycan and Lipoteichoic Acid, are thought to contribute to the development of sepsis and MODS. In this review, the literature underlying our current understanding of how peptidoglycan and Lipoteichoic Acid activate inflammatory responses will be presented, with a focus on recent advances in this field.
Jacob E Wang - One of the best experts on this subject based on the ideXlab platform.
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peptidoglycan and Lipoteichoic Acid in gram positive bacterial sepsis receptors signal transduction biological effects and synergism
Shock, 2003Co-Authors: Jacob E Wang, Maria K Dahle, Michelle C Mcdonald, Simon J Foster, A O Aasen, Christoph ThiemermannAbstract:In sepsis and multiple organ dysfunction syndrome (MODS) caused by gram-negative bacteria, lipopoly- saccharide (LPS) initiates the early signaling events leading to the deleterious inflammatory response. However, it has become clear that LPS can not reproduce all of the clinical features of sepsis, which emphasize the roles of other contributing factors. Gram-positive bacteria, which lack LPS, are today responsible for a substantial part of the incidents of sepsis with MODS. The major wall components of gram-positive bacteria, peptidoglycan and Lipoteichoic Acid, are thought to contribute to the development of sepsis and MODS. In this review, the literature underlying our current understanding of how peptidoglycan and Lipoteichoic Acid activate inflammatory responses will be presented, with a focus on recent advances in this field. KEYWORDS—Gram-positive bacteria, sepsis, MODS, cytokines, peptidoglycan, Lipoteichoic Acid
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peptidoglycan and Lipoteichoic Acid in gram positive bacterial sepsis receptors signal transduction biological effects and synergism
Shock, 2003Co-Authors: Jacob E Wang, Maria K Dahle, Michelle C Mcdonald, Simon J Foster, A O Aasen, Christoph ThiemermannAbstract:In sepsis and multiple organ dysfunction syndrome (MODS) caused by gram-negative bacteria, lipopolysaccharide (LPS) initiates the early signaling events leading to the deleterious inflammatory response. However, it has become clear that LPS can not reproduce all of the clinical features of sepsis, which emphasize the roles of other contributing factors. Gram-positive bacteria, which lack LPS, are today responsible for a substantial part of the incidents of sepsis with MODS. The major wall components of gram-positive bacteria, peptidoglycan and Lipoteichoic Acid, are thought to contribute to the development of sepsis and MODS. In this review, the literature underlying our current understanding of how peptidoglycan and Lipoteichoic Acid activate inflammatory responses will be presented, with a focus on recent advances in this field.
Maria K Dahle - One of the best experts on this subject based on the ideXlab platform.
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peptidoglycan and Lipoteichoic Acid in gram positive bacterial sepsis receptors signal transduction biological effects and synergism
Shock, 2003Co-Authors: Jacob E Wang, Maria K Dahle, Michelle C Mcdonald, Simon J Foster, A O Aasen, Christoph ThiemermannAbstract:In sepsis and multiple organ dysfunction syndrome (MODS) caused by gram-negative bacteria, lipopoly- saccharide (LPS) initiates the early signaling events leading to the deleterious inflammatory response. However, it has become clear that LPS can not reproduce all of the clinical features of sepsis, which emphasize the roles of other contributing factors. Gram-positive bacteria, which lack LPS, are today responsible for a substantial part of the incidents of sepsis with MODS. The major wall components of gram-positive bacteria, peptidoglycan and Lipoteichoic Acid, are thought to contribute to the development of sepsis and MODS. In this review, the literature underlying our current understanding of how peptidoglycan and Lipoteichoic Acid activate inflammatory responses will be presented, with a focus on recent advances in this field. KEYWORDS—Gram-positive bacteria, sepsis, MODS, cytokines, peptidoglycan, Lipoteichoic Acid
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peptidoglycan and Lipoteichoic Acid in gram positive bacterial sepsis receptors signal transduction biological effects and synergism
Shock, 2003Co-Authors: Jacob E Wang, Maria K Dahle, Michelle C Mcdonald, Simon J Foster, A O Aasen, Christoph ThiemermannAbstract:In sepsis and multiple organ dysfunction syndrome (MODS) caused by gram-negative bacteria, lipopolysaccharide (LPS) initiates the early signaling events leading to the deleterious inflammatory response. However, it has become clear that LPS can not reproduce all of the clinical features of sepsis, which emphasize the roles of other contributing factors. Gram-positive bacteria, which lack LPS, are today responsible for a substantial part of the incidents of sepsis with MODS. The major wall components of gram-positive bacteria, peptidoglycan and Lipoteichoic Acid, are thought to contribute to the development of sepsis and MODS. In this review, the literature underlying our current understanding of how peptidoglycan and Lipoteichoic Acid activate inflammatory responses will be presented, with a focus on recent advances in this field.