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Teichoic Acids and Related Cell-Wall Glycopolymers in Gram-Positive Physiology and Host Interactions

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Teichoic Acids and Related Cell-Wall Glycopolymers in Gram-Positive Physiology and Host Interactions REVIEWS Teichoic acids and related cell-wall glycopolymers in Gram-positive physiology and host interactions Christopher Weidenmaier* and Andreas Peschel‡ Abstract | Most Gram-positive bacteria incorporate membrane- or peptidoglycan-attached carbohydrate-based polymers into their cell envelopes. Such cell-wall glycopolymers (CWGs) often have highly variable structures and have crucial roles in protecting, connecting and controlling the major envelope constituents. Further important roles of CWGs in host-cell adhesion, inflammation and immune activation have also been described in recent years. Identifying and harnessing highly conserved or species-specific structural features of CWGs offers excellent opportunities for developing new antibiotics, vaccines and diagnostics for use in the fight against severe infectious diseases, such as sepsis, pneumonia, anthrax and tuberculosis. Capsular polysaccharide The Gram-negative cell envelope comprises a thin detailed analysis of the physiological functions of 15–17 A glycopolymer, usually of peptidoglycan sacculus that is covered by an outer CWGs . Moreover, an increasing body of evidence variable composition and membrane. By contrast, Gram-positive bacteria have indicates that certain CWGs have important roles in structure, that forms capsule- developed a profoundly different cell-envelope struc- infections caused by major human pathogens, such like protective layers around ture; they lack the normal outer membrane, and the as Staphylococcus aureus, Streptococcus pneumoniae, microbial cells. cell wall is usually much thicker than that of Gram- Bacillus anthracis and Mycobacterium tuberculosis, S-layer protein negative species, with multiple peptidoglycan layers1,2. and they are, therefore, important candidate tar- Forms a crystalline two- In addition, most Gram-positive bacteria possess gets for novel anti-infective drugs, vaccines and dimensional lattice on other protective surface structures. These are highly diagnostics (FIG. 1). microbial-cell surfaces. variable and include capsular polysaccharides, S-layer The structures of CWGs are highly diverse and proteins, mycolic acids that form an outer-membrane- often species- or even strain-specific. Most Gram- like structure (in certain Actinobacteria) or com- positive bacteria have two types of CWG, one binations of these elements. One constant motif of peptidoglycan-attached and one lipid-attached7,12, Gram-positive cell envelopes, however, is the pres- although some bacterial species have three or four ence of additional glycopolymers, which form part of different CWGs. Bacillus subtilis, for example, has one the fabric of the cell wall and are attached either to the lipoteichoic acid (LTA), two distinct wall teichoic acids *Channing Laboratory, peptidoglycan or to membrane lipids3–11 (FIG. 1). These (WTAs) and one teichuronic acid, which is expressed Brigham and Women’s cell-wall glycopolymers (CWGs) include the teichoic only under low-phosphate conditions18. CWGs differ Hospital and Harvard acids Medical School, Boston, , which are probably the best studied type of according to their type of sugar, net charge and deco- 7,12 Massachusetts 02115, USA. CWG ; the ‘secondary cell-wall polysaccharides’, ration of the repeating units (FIG. 2). The backbone can ‡Cellular and Molecular which are found in many bacilli and their relatives9; contain sugars of various sizes that range from trioses Microbiology Section, and the branched mycobacterial arabinose-containing to hexoses, which can be reduced (polyols) or oxidized Medical Microbiology and 13 uronic acids Hygiene Department, polymers . ( ) and can adopt pyranose or furanose University of Tübingen, Our knowledge of the diversity, structure and configurations. In addition to CWGs, Gram-positive 72076 Tübingen, Germany. function of CWGs is still far from complete. Teichoic cell envelopes can contain many other glycosylated Correspondence to A.P. acids were discovered in the 1950s by James Baddiley molecules that, together, form a major constituent of e-mail: andreas.peschel and co-workers14 and were assumed to have important the cellular biomass (BOX 1). @uni-tuebingen.de doi:10.1038/nrmicro1861 roles in Gram-positive cell envelopes. However, only This Review summarizes recent findings on the Published online in recent years have mutants without or with altered functions of CWGs and discusses common functional 10 March 2008 CWGs become available, which has enabled a more themes that have begun to emerge. 276 | APril 2008 | VolUME 6 www.nature.com/reviews/micro © 2008 Nature Publishing Group REVIEWS Staphylococcus aureus Streptococcus pneumoniae Bacillus anthracis Mycobacterium tuberculosis Mycolic acids S-LP S-LP CBP CBP CBP CBP CBP CBP CBP CBP CBP Figure 1 | Cell-wall glycopolymers (CWGs) in the cell walls of major human pathogens. CWG polymers are shown as chains of circles within the cell wall. Differences in the composition of CWG repeating units areNatur indicatede Reviews by | differentMicrobiology colours. Linkage units that connect CWGs with peptidoglycan or lipids are shown as dark- or light-grey circles, respectively. See FIG. 2 for compositional details. CWGs connect choline-binding proteins (CBPs) in S. pneumoniae, S-layer proteins (S-LPs) in B. anthracis and mycolic acids in M. tuberculosis. Bacilli and mycobacteria often contain more than the two types of CWG shown here. Mycolic acid Different types of CWG modified with d-alanine7, whereas acetyl, glutamyl Very-long-chain fatty acid that contains up to 60 carbon atoms It is beyond the scope of this article to provide a and lysyl modifications have been described in WTAs 22,25 and unusual modifications that comprehensive overview of the full structural diver- from high-G+C Gram-positive bacteria . form an outer-membrane-like sity of CWGs (for more detailed reviews, see REFS layer on the surface of 3–6,8,9,11). Peptidoglycan-anchored CWGs (P-CWGs) Anionic CWGs. Many Gram-positive bacteria produce mycobacteria and their relatives. Mycolic acids are are connected to the cell wall by phosphodiester bonds polyanionic CWGs, which lack phosphate groups in responsible for mycobacterial between N-acetylmuramic acid and a special linkage their polymer backbone and do not, therefore, belong surface hydrophobicity and unit that is often formed by an N-acetylglucosamine– to the classical teichoic acids (FIG. 2). Teichuronic acid resistance to most conventional N-acetylmannosamine disaccharide19. Membrane- is produced instead of WTA by B. subtilis, other bacilli antibiotics. connected CWGs (M-CWGs) are attached to glycolipids and micrococci under conditions of phosphate limita- 12 (FIG. 2) Teichoic acid of varying size and composition . As the cur- tion. Their anionic properties result from the presence 4,26 A cell-envelope glycopolymer rent nomenclature of CWGs is often ambiguous and of uronic acids . The secondary cell-wall polysac- that is composed of many confusing, in this Review, we suggest a classification charides of the P‑CWG type from certain members of identical sugar-phosphate system that is based on their electrostatic properties the Bacillaceae are polyanionic because of their modi- repeating units, which are rather than their chemical composition. fication with pyruvyl groups9. The structure of such a usually modified with D-alanine 27 and additional sugars. CWG from B. anthracis has recently been determined . Zwitterionic CWGs. The presence of phosphate in Pyruvylated CWGs seem to be integral cell-wall com- Lipoteichoic acid (LTA) CWG repeating units is the hallmark of the ‘classi- ponents in bacteria that possess S-layer proteins with A teichoic acid species that is cal’ teichoic acids. Most teichoic acids have zwitteri- an S-layer homology domain that binds CWGs in a connected to membrane onic 9,28 glycolipids. The properties because of the presence of negatively pyruvylation-dependent manner . Micrococcus luteus, stereochemistry of LTAs and charged phosphate groups and modifications with Mycobacterium bovis and other bacteria of the high-G+C the biosynthetic origin of the free amino groups that are contained in residues such branch of Gram-positive bacteria produce lipoglycans glycerolphosphates are as d-alanine7,20. Peptidoglycan-attached WTAs are that are esterified with anionic succinyl groups24,29,30. different from those of wall teichoic acids, which have frequently formed by glycerol or ribitol groups that Some atypical teichoic acids, such as the minor WTA glycerol-phosphate backbones. are connected by phosphodiester bonds (for example, of B. subtilis, contain only negatively charged phosphate in S. aureus), but tetroses, hexoses or complex sugar groups and positive charges are absent31. Teichuronic acid combinations have also been described (for example, A teichoic acid-like polymer in S. pneumoniae)11,21–23. Uncharged CWGs. Uncharged CWGs have been that lacks phosphate groups and possesses polyanionic The membrane-anchored LTAs are usually less described in many actinomycetes, such as mycobac- 13,32,33 properties because of the diverse than WTAs, which is probably due to the teria, corynebacteria and rhodococci . Many of presence of uronic acid- peculiar LTA biosynthetic pathway (discussed below)6,12. these polymers seem to be branched and contain containing repeating units. LTA polymers are usually formed by glycerol-phosphate mannose, arabinose and/or galactose. The peptidogly- Uronic acid repeating units and are connected to glycolipids. can-anchored mycobacterial arabinogalactans are cov- 8,34 A sugar-derived
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