Wall Teichoic Acid Function, Biosynthesis, and Inhibition

Swoboda, Jonathan G.; Campbell, Jennifer; Meredith, Timothy C.; Walker, Suzanne

doi:10.1002/cbic.200900557

Cited by 347 publications

(370 citation statements)

References 94 publications

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“…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%

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%

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

Fong¹,

Kajihara²,

Chen³

et al. 2018

mAbs

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“…Once synthesis is complete, the polymer is exported by TagGH to the outside of the cell, where it is attached to the 6-hydroxyl of N-acetylmuramic acid of peptidoglycan by an unknown transferase and modified with cationic D-alanyl esters ( Fig. 1) (4,13). Significant gaps still remain, however, in our understanding of wall teichoic acid synthesis, most notably in relation to wall teichoic acid glycosylation.…”

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confidence: 99%

Studies of the Genetics, Function, and Kinetic Mechanism of TagE, the Wall Teichoic Acid Glycosyltransferase in Bacillus subtilis 168

Allison

D’Elia

Arar

et al. 2011

Journal of Biological Chemistry

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The biosynthetic enzymes involved in wall teichoic acid biogenesis in Gram-positive bacteria have been the subject of renewed investigation in recent years with the benefit of modern tools of biochemistry and genetics. Nevertheless, there have been only limited investigations into the enzymes that glycosylate wall teichoic acid. Decades-old experiments in the model Gram-positive bacterium, Bacillus subtilis 168, using phage-resistant mutants implicated tagE (also called gtaA and rodD) as the gene coding for the wall teichoic acid glycosyltransferase. This study and others have provided only indirect evidence to support a role for TagE in wall teichoic acid glycosylation. In this work, we showed that deletion of tagE resulted in the loss of ␣-glucose at the C-2 position of glycerol in the poly(glycerol phosphate) polymer backbone. We also reported the first kinetic characterization of pure, recombinant wall teichoic acid glycosyltransferase using clean synthetic substrates. We investigated the substrate specificity of TagE using a wide variety of acceptor substrates and found that the enzyme had a strong kinetic preference for the transfer of glucose from UDP-glucose to glycerol phosphate in polymeric form. Further, we showed that the enzyme recognized its polymeric (and repetitive) substrate with a sequential kinetic mechanism. This work provides direct evidence that TagE is the wall teichoic acid glycosyltransferase in B. subtilis 168 and provides a strong basis for further studies of the mechanism of wall teichoic acid glycosylation, a largely uncharted aspect of wall teichoic acid biogenesis.

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“…The mechanism by which TarS modulates the MRSA phenotype is also of interest, especially as the precise functions of TA still remain elusive (11). Whereas TA null mutants are defective in cell division (4, 9), tarS and tarM mutants (and a tarS tarM double mutant) of S. aureus MW2 are not (4).…”

Section: Reversing Resistance Can Prolong Antibiotic Utilitymentioning

confidence: 99%

“…Now that situation is changing, and there is a growing momentum to studies into their biosynthesis and their contributions to bacterial physiology (10,11,15). Further collaborations between biochemists, biophysicists, geneticists, microbiologists, and structural biologists will be needed to unravel the fine details of TA function.…”

Section: Reversing Resistance Can Prolong Antibiotic Utilitymentioning

confidence: 99%