Teichoic acids and related cell-wall glycopolymers in Gram-positive physiology and host interactions

Weidenmaier, Christopher; Peschel, Andreas

doi:10.1038/nrmicro1861

Cited by 647 publications

(600 citation statements)

References 164 publications

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“…Anti-infective biologics with novel mechanisms of action targeting S. aureus alpha toxin, 9,10 protective antigen of Bacillus anthracis , 11 toxins A and B from Clostridium difficile , 12 and Pseudomonas aeruginosa cell wall components 13,14 are currently approved or in clinical development. The presence of cell wall glycopolymers, particularly in Gram-positive bacteria, shields many epitopes that might confer bactericidal activity from antibodies and other host-defense molecules, 15 but these cell wall polysaccharides also represent a potential target for mAb therapeutics. An important component of immune defenses against bacteria is a repertoire of germline “natural antibodies” that have affinity for non-protein bacterial epitopes such as carbohydrates.…”

Section: Introductionmentioning

confidence: 99%

“…15 WTA varies in structure from species to species, with the S. aureus WTA molecule consisting of a short polysaccharide “linkage unit” connected to a N-acetylmuramic acid residue within the peptidoglycan layer, followed by an extended ribitol poly-phosphate polymer 23 (Figure 1). Decorating each ribitol at the 2- and 4-position carbon atoms are an α- or β-linked N-acetylglucosamine (α/β-O-GlcNAc), respectively, and an ester-linked D-alanine (D-alanyl ester).…”

Section: Introductionmentioning

confidence: 99%

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Structural investigation of humanS. aureus-targeting antibodies that bind wall teichoic acid

Fong¹,

Kajihara²,

Chen³

et al. 2018

mAbs

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Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a growing health threat worldwide. Efforts to identify novel antibodies that target S. aureus cell surface antigens are a promising direction in the development of antibiotics that can halt MRSA infection. We biochemically and structurally characterized three patient-derived MRSA-targeting antibodies that bind to wall teichoic acid (WTA), which is a polyanionic surface glycopolymer. In S. aureus, WTA exists in both α- and β-forms, based on the stereochemistry of attachment of a N-acetylglucosamine residue to the repeating phosphoribitol sugar unit. We identified a panel of antibodies cloned from human patients that specifically recognize the α or β form of WTA, and can bind with high affinity to pathogenic wild-type strains of S. aureus bacteria. To investigate how the β-WTA specific antibodies interact with their target epitope, we determined the X-ray crystal structures of the three β-WTA specific antibodies, 4462, 4497, and 6078 (Protein Data Bank IDs 6DWI, 6DWA, and 6DW2, respectively), bound to a synthetic WTA epitope. These structures reveal that all three of these antibodies, while utilizing distinct antibody complementarity-determining region sequences and conformations to interact with β-WTA, fulfill two recognition principles: binding to the β-GlcNAc pyranose core and triangulation of WTA phosphate residues with polar contacts. These studies reveal the molecular basis for targeting a unique S. aureus cell surface epitope and highlight the power of human patient-based antibody discovery techniques for finding novel pathogen-targeting therapeutics.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural investigation of humanS. aureus-targeting antibodies that bind wall teichoic acid

Fong¹,

Kajihara²,

Chen³

et al. 2018

mAbs

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“…WTAs and their lipid-linked versions (lipoteichoic acids) have a wide range of important cellular roles including control of autolytic activity, antigenicity and innate immune recognition, pathogenicity, biofilm formation, efficient release of secreted proteins into the culture medium, cation homoeostasis, antibiotic resistance, and cell elongation and division (summarized in Weidenmaier and Peschel, 2008).…”

Section: Introductionmentioning

confidence: 99%

A widespread family of bacterial cell wall assembly proteins

et al. 2011

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Teichoic acids and acidic capsular polysaccharides are major anionic cell wall polymers (APs) in many bacteria, with various critical cell functions, including maintenance of cell shape and structural integrity, charge and cation homeostasis, and multiple aspects of pathogenesis. We have identified the widespread LytR-Cps2A-Psr (LCP) protein family, of previously unknown function, as novel enzymes required for AP synthesis. Structural and biochemical analysis of several LCP proteins suggest that they carry out the final step of transferring APs from their lipid-linked precursor to cell wall peptidoglycan (PG). In Bacillus subtilis, LCP proteins are found in association with the MreB cytoskeleton, suggesting that MreB proteins coordinate the insertion of the major polymers, PG and AP, into the cell wall.

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“…Teichoic or teichuronic acids are typical and well‐studied SCWP in Gram‐positive bacteria and play an important role in normal cell function and infection (Weidenmaier and Peschel, 2008). Many β‐hemolytic streptococcal species appear to lack expression of typical teichoic or teichuronic acid structures (Sutcliffe et al ., 2008; Caliot et al ., 2012) and instead express a rhamnose‐rich polymer, which comprises approximately half of the cell wall mass (McCarty, 1952).…”

Section: Introductionmentioning

confidence: 99%

GacA is essential for Group A Streptococcus and defines a new class of monomeric dTDP‐4‐dehydrorhamnose reductases (RmlD)

Beek

Breton

Ferenbach

et al. 2015

Molecular Microbiology

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SummaryThe sugar nucleotide dTDP‐L‐rhamnose is critical for the biosynthesis of the Group A Carbohydrate, the molecular signature and virulence determinant of the human pathogen Group A S treptococcus (GAS). The final step of the four‐step dTDP‐L‐rhamnose biosynthesis pathway is catalyzed by dTDP‐4‐dehydrorhamnose reductases (RmlD). RmlD from the Gram‐negative bacterium S almonella is the only structurally characterized family member and requires metal‐dependent homo‐dimerization for enzymatic activity. Using a biochemical and structural biology approach, we demonstrate that the only RmlD homologue from GAS, previously renamed GacA, functions in a novel monomeric manner. Sequence analysis of 213 Gram‐negative and Gram‐positive RmlD homologues predicts that enzymes from all Gram‐positive species lack a dimerization motif and function as monomers. The enzymatic function of GacA was confirmed through heterologous expression of gac A in a S. mutans rml D knockout, which restored attenuated growth and aberrant cell division. Finally, analysis of a saturated mutant GAS library using Tn‐sequencing and generation of a conditional‐expression mutant identified gac A as an essential gene for GAS. In conclusion, GacA is an essential monomeric enzyme in GAS and representative of monomeric RmlD enzymes in Gram‐positive bacteria and a subset of Gram‐negative bacteria. These results will help future screens for novel inhibitors of dTDP‐L‐rhamnose biosynthesis.

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Teichoic acids and related cell-wall glycopolymers in Gram-positive physiology and host interactions

Cited by 647 publications

References 164 publications

Structural investigation of humanS. aureus-targeting antibodies that bind wall teichoic acid

Structural investigation of humanS. aureus-targeting antibodies that bind wall teichoic acid

A widespread family of bacterial cell wall assembly proteins

GacA is essential for Group A Streptococcus and defines a new class of monomeric dTDP‐4‐dehydrorhamnose reductases (RmlD)

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