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Elucidating Peptidoglycan Structure: an Analytical Toolset

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Elucidating Peptidoglycan Structure: an Analytical Toolset Trends in Microbiology Review Elucidating Peptidoglycan Structure: An Analytical Toolset Sara Porfírio,1 Russell W. Carlson,1 and Parastoo Azadi1,* Peptidoglycan (PG) is a ubiquitous structural polysaccharide of the bacterial cell Highlights wall, essential in preserving cell integrity by withstanding turgor pressure. Any PG is a major bacterial cell wall compo- change that affects its biosynthesis or degradation will disturb cell viability, nent, crucial for cell integrity, and strongly therefore PG is one of the main targets of antimicrobial drugs. Considering its related to antibiotic sensitivity. major role in cell structure and integrity, the study of PG is of utmost relevance, Methods to analyze PG structure have with prospective ramifications to several disciplines such as microbiology, phar- evolved over time, and new and im- macology, agriculture, and pathogenesis. Traditionally, high-performance liquid proved methods are currently replacing chromatography (HPLC) has been the workhorse of PG analysis. In recent years, previous tedious and long procedures. technological and bioinformatic developments have upgraded this seminal Current tools, ranging from technique, making analysis more sensitive and efficient than ever before. Here chromatography–mass spectrometry we describe a set of analytical tools for the study of PG structure (from composi- methods to imaging techniques, allow tion to 3D architecture), identify the most recent trends, and discuss future characterizing PG from a structural and architectural perspective. challenges in the field. Peptidoglycan Structure and Diversity Peptidoglycan (PG) (also known as murein, from Latin ‘murus’, wall) is a major component of the bacterial cell wall [1] (Figure 1). Present in both Gram-positive and Gram-negative bacteria [2], this polysaccharide forms a flexible, net-like structure that determines cell shape and provides mechanical strength and osmotic stability. Although the structure and architecture of PG has been studied for a long time (for reviews see [3–5]), its detailed 3D structure is still an open question [5,6]. PG is a heteropolymer of linear glycan (see Glossary) strands crosslinked by short peptide brid- ges (Figure 2). The glycan strands are formed by repeating units of the disaccharide β-1,4-linked N-acetylglucosamine–N-acetylmuramic acid (GlcNAc-MurNAc). In Gram-negative bacteria the glycan strands end with a 1,6-anhydro-MurNAc residue, which results from the action of lytic transglycosylases [7]. Chemical variation of the glycan strands – for example, O-acetylation, O-glycolylation, and de-N-acetylation of GlcNAc, MurNAc, or both – is one of the sources of PG diversity, and some of these modifications have been related to changes in antibiotic sensitiv- ity [8]. Another source of diversity in PG structure is due to variation of the peptide moiety [4].In fact, the amino acid composition of PG stem peptides has been characterized in many species and is the basis for the PG bacterial classification system proposed by Schleifer and Kandler [9] that is still used today. These PG stem peptides are formed by five amino acids with L- and D-configurations, attached to the lactyl groups of MurNAc by an amide linkage [3].Theyare crosslinked to each other through the second amino group of the diamino acid present at 1Complex Carbohydrate Research positions two or three of the peptide chain (Figure 2). In Gram-negative bacteria, the stem Center, The University of Georgia, 315 peptide is a L-Ala–D-iGlu–m-DAP–D-Ala–D-Ala pentapeptide, where iGlu and m-DAP corre- Riverbend Road, Athens, GA, 30602, USA spond to iso-glutamate and meso-diaminopimelic acid, respectively. This PG chemotype has been named A1γ and is rarely found in Gram-positive bacteria [10], where often the D-iGlu resi- due at position two is amidated, resulting in D-iGln, and L-Lys replaces m-DAP at position *Correspondence: three [11].Asidefromamidation, the formation of cyclic imides in the peptide stem has also [email protected] (P. Azadi). Trends in Microbiology, July 2019, Vol. 27, No. 7 https://doi.org/10.1016/j.tim.2019.01.009 607 Published by Elsevier Ltd. Trends in Microbiology 608 Trends in Microbiology, July 2019, Vol. 27, No. 7 Trends in Microbiology Figure 1. Cell Wall Structure of Gram-Positive and Gram-Negative Bacteria. (Left) Gram-negative bacteria display a complex cell wall formed by two lipid bilayers (inner and outer membranes) which enclose the periplasmic space where peptidoglycan (PG) is located. In this case, PG forms a thin layer that surrounds the cell and it is tethered to both cell membranes by lipoproteins. The outer membrane is permeated by porins – proteins that cross the cell membrane and act as a pore, through which molecules can diffuse – and decorated with lipopolysaccharides (LPS). LPS, also referred to as endotoxin, is the major surface component of Gram-negative bacteria, contributing greatly to the structural integrity of the cell, and represents one of the microbial molecular signals responsible for activation of the host innate immune system. (Center) Gram-positive bacteria are surrounded by a single cell membrane and possess a much thicker layer of PG than Gram-negatives. Similarly, PG is attached to the cell membrane through a lipoprotein. Gram-positives also functionalize their cell wall with non-PG surface polymers. Teichoic acids and lipoteichoic acids are the main cell wall-bound polymers in Gram-positive bacteria and they play crucial roles in cell shape determination, regulation of cell division, pathogenesis, and antibiotic resistance. (Right) Acid-fast bacteria, such as mycobacteria, are a subset of Gram-positive bacteria with highly complex cell walls. While teichoic acids and lipoteichoic acids are not found in this group of organisms, their cell envelope is formed by a large macromolecular structure, termed the mycolylarabinogalactan- peptidoglycan (mAGP) complex. The mAGP complex is formed by characteristic long-chain mycolic acids, a highly branched arabinogalactan (AG) polysaccharide, and a crosslinked PG network. In addition, an outer membrane segment that contains solvent-extractable lipids, such as lipoarabinomannan (LAM) and other glycolipids, completes the cell wall. Monosaccharides shown in this figure follow the Symbol Nomenclature for Graphical Representation of Glycans (https://www.ncbi.nlm.nih.gov/glycans/snfg.html). Trends in Microbiology Aachment of Possible modificaons of glycan chains surface polymers (ex: teichoic acids) Unmodified SP SP O-acetylaon O LU disaccharide N-deacetylaon - N-glycolylaon O P O O (GlcNAc – MurNAc) Muramic δ-lactam (at MurNAc) - 1,6-anhydro-MurNAc (GlcN, MurN or both) (at MurN) O O P O CH3 HO HO OH OH LU O O L-Hse OH OH OH OH OH OH OH OH OH OH OH OH OH CO OH O O O O O O O O O O O O O O O O O O O O O O O O O O O O O OH O O O O O O O O O O O O O O O NH HO NH O + HO NH NH HO NH O NH HO NH NH HO + NH HO NH NH HO NH HO NH HO NH NH HO NH NH O O O O H C O D-Ala NH3 O 3 NH O HO NH O O NH O O O O H C O 3 O O H C O O O O O O NH O H C O H3C O H C O H3C 3 H3C O 3 H3C 3 O 3 CH H3C CH 3 CO CH CH CH CH3 CH3 3 3 CH CH3 CH3 CH CH2OH CH CH CO CH CH CH 3 3 COOH 3 COOH OC 3 CH3 COOH 3 3 CH3 3 COOH 3 3 OC OC CH O COOH 3 NH NH HN HN L-Ala NH O O O HN HN O O NH O NH O O Pepde bridge Direct 3-3 cross-link m Direct 3-4 O O HN -DAP Ornithine bridge O O O O m m OH HN 3-4 cross-link HO ( -DAP- -DAP) HN OH O cross-link O O O HO HO OH 2-4 cross-link O O HN O HN HO H O HN O HN O L-Lys HN O NH O NH N NH2 HO NH O 2 NH N HN H O O N NH O N H H N HN O HN H NH2 O OH O O HN O HO HN NH O O NH O NH HO HO O HN Direct 1-3 O O HN D-Glu HO OH O NH O OH O O HN cross-link HO HO O H2N O HN OH OH HO O O HO O NH HN Gly O O HN Stem pepdes Stem O O O O HN NH NH NH HN D-Orn O NH COOH CO OC COOH CH3 CH3 COOH COOH COOH CO OC CH3 CH3 CH CH CH CH CH CH CH CH CH3 CH 3 3 CO 3 3 COOH CH CH CH CH CH 3 3 3 3 CH3 CH 3 O O CH3 3 3 3 3 3 3 H C O H C O O O H C H C O H C O H C O H C O HO 3 NH HO NH 3 3 O O O O O H C O H3C O 3 O O 3 O O 3 O 3 O O NH HO NH NH HO NH H C O NH NH O O 3 O O O O NH HO NH NH HO NH O NH NH 3 HO H3C O NH HO NH NH HO NH NH HO NH NH HO NH O O O O O O O O O O O OH O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O HO HO HO HO HO HO OH HO HO HO OH OH OH OH OH OH OH OH OH OH OH OH PG structure in Gram-negave bacteria PG structure in Gram-posive bacteria Other modificaons Terminal 1,6-anhydro MurNAc residues OH OH OH OH OH O OH OH OH OH OH OH O O O O O O O O O O O O O O O O O O O OH O O O OH HO NH HO NH NH HO NH O NH HO NH O HO NH NH NH HO NH O NH O O O O O O NH O O O O O H C O H C H3C H C H3C O O 3 3 3 O H C CH CH CH 3 CH 3 3 CH3 COOH 3 CH3 CH3 CH CH3 3 COOH CH3 OC COOH CH CO 3 OC CH3 3 NH NH HN O Pentaglycine bridge O O O NH Direct 3-4 HN O H D-iGlu at H N NH N N O O O cross-linkage D-iGln at O H posion 2 NH2 O O O posion 2 O O HO HO NH NH NH2 NH N O H O m H N NH -DAP at O Amidaon N 2 O H posion 3 HN O NH O HN O O HN NH2 O O HO O L-Lys at O NH O H2N N HN OH posion 3 NH HO O 2 HO O O OH HN O O NH Cyclic imide A1γ chemotype O O HN formaon NH OC CH COOH COOH CH3 CH3 3 CH3 CH3 COOH CH3 CH3 CH3 CH3 CO CH3 O H O O HO 3C O O O O O H3C O NH HO NH H C O O O NH NH HO NH H C O NH NH O 3 NH HO NH 3 HO H3C O NH O O O Described in E.
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