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EcoSal Plus Jan 2021Peptidoglycan is a defining feature of the bacterial cell wall. Initially identified as a target of the revolutionary beta-lactam antibiotics, peptidoglycan has become a...
Peptidoglycan is a defining feature of the bacterial cell wall. Initially identified as a target of the revolutionary beta-lactam antibiotics, peptidoglycan has become a subject of much interest for its biology, its potential for the discovery of novel antibiotic targets, and its role in infection. Peptidoglycan is a large polymer that forms a mesh-like scaffold around the bacterial cytoplasmic membrane. Peptidoglycan synthesis is vital at several stages of the bacterial cell cycle: for expansion of the scaffold during cell elongation and for formation of a septum during cell division. It is a complex multifactorial process that includes formation of monomeric precursors in the cytoplasm, their transport to the periplasm, and polymerization to form a functional peptidoglycan sacculus. These processes require spatio-temporal regulation for successful assembly of a robust sacculus to protect the cell from turgor and determine cell shape. A century of research has uncovered the fundamentals of peptidoglycan biology, and recent studies employing advanced technologies have shed new light on the molecular interactions that govern peptidoglycan synthesis. Here, we describe the peptidoglycan structure, synthesis, and regulation in rod-shaped bacteria, particularly , with a few examples from and other diverse organisms. We focus on the pathway of peptidoglycan sacculus elongation, with special emphasis on discoveries of the past decade that have shaped our understanding of peptidoglycan biology.
Topics: Cell Division; Cell Membrane; Cell Wall; Escherichia coli; Peptidoglycan
PubMed: 33470191
DOI: 10.1128/ecosalplus.ESP-0010-2020 -
Microbiology Spectrum May 2019has a complex cell wall that plays key roles in cell shape maintenance, growth and cell division, and interactions with components of the human host. The peptidoglycan... (Review)
Review
has a complex cell wall that plays key roles in cell shape maintenance, growth and cell division, and interactions with components of the human host. The peptidoglycan has a heterogeneous composition with more than 50 subunits (muropeptides)-products of several peptidoglycan-modifying enzymes. The amidation of glutamate residues in the stem peptide is needed for efficient peptide cross-linking, and peptides with a dipeptide branch prevail in some beta-lactam-resistant strains. The glycan strands are modified by deacetylation of -acetylglucosamine residues and -acetylation of -acetylmuramic acid residues, and both modifications contribute to pneumococcal resistance to lysozyme. The glycan strands carry covalently attached wall teichoic acid and capsular polysaccharide. Pneumococci are unique in that the wall teichoic acid and lipoteichoic acid contain the same unusually complex repeating units decorated with phosphoryl choline residues, which anchor the choline-binding proteins. The structures of lipoteichoic acid and the attachment site of wall teichoic acid to peptidoglycan have recently been revised. During growth, pneumococci assemble their cell walls at midcell in coordinated rounds of cell elongation and division, leading to the typical ovococcal cell shape. Cell wall growth depends on the cytoskeletal FtsA and FtsZ proteins and is regulated by several morphogenesis proteins that also show patterns of dynamic localization at midcell. Some of the key regulators are phosphorylated by StkP and dephosphorylated by PhpP to facilitate robust selection of the division site and plane and to maintain cell shape.
Topics: Acetylation; Acetylglucosamine; Bacterial Proteins; Cell Cycle; Cell Division; Cell Wall; Choline; Cytoskeletal Proteins; Humans; Lipopolysaccharides; Muramic Acids; Muramidase; Operon; Penicillin Resistance; Peptidoglycan; Phosphorylation; Polysaccharides; Streptococcus pneumoniae; Teichoic Acids; beta-Lactam Resistance
PubMed: 31172911
DOI: 10.1128/microbiolspec.GPP3-0018-2018 -
Viruses Apr 2021Antibiotic-resistant pathogens are increasingly more prevalent and problematic. Traditional antibiotics are no longer a viable option for dealing with these... (Review)
Review
Antibiotic-resistant pathogens are increasingly more prevalent and problematic. Traditional antibiotics are no longer a viable option for dealing with these multidrug-resistant microbes and so new approaches are needed. Bacteriophage-derived proteins such as endolysins could offer one effective solution. Endolysins are bacteriophage-encoded peptidoglycan hydrolases that act to lyse bacterial cells by targeting their cell's wall, particularly in Gram-positive bacteria due to their naturally exposed peptidoglycan layer. These lytic enzymes have received much interest from the scientific community in recent years for their specificity, mode of action, potential for engineering, and lack of resistance mechanisms. Over the past decade, a renewed interest in endolysin therapy has led to a number of successful applications. Recombinant endolysins have been shown to be effective against prominent pathogens such as MRSA, strains in biofilm formation, and . Endolysins have also been studied in combination with other antimicrobials, giving a synergistic effect. Although endolysin therapy comes with some regulatory and logistical hurdles, the future looks promising, with the emergence of engineered "next-generation" lysins. This review will focus on the likelihood that endolysins will become a viable new antimicrobial therapy and the challenges that may have to be overcome along the way.
Topics: Animals; Bacteriophages; Cell Wall; Endopeptidases; Gram-Positive Bacterial Infections; Humans; Peptidoglycan; Phage Therapy
PubMed: 33920965
DOI: 10.3390/v13040680 -
PLoS Pathogens Sep 2017Lysozyme is a cornerstone of innate immunity. The canonical mechanism for bacterial killing by lysozyme occurs through the hydrolysis of cell wall peptidoglycan (PG).... (Review)
Review
Lysozyme is a cornerstone of innate immunity. The canonical mechanism for bacterial killing by lysozyme occurs through the hydrolysis of cell wall peptidoglycan (PG). Conventional type (c-type) lysozymes are also highly cationic and can kill certain bacteria independently of PG hydrolytic activity. Reflecting the ongoing arms race between host and invading microorganisms, both gram-positive and gram-negative bacteria have evolved mechanisms to thwart killing by lysozyme. In addition to its direct antimicrobial role, more recent evidence has shown that lysozyme modulates the host immune response to infection. The degradation and lysis of bacteria by lysozyme enhance the release of bacterial products, including PG, that activate pattern recognition receptors in host cells. Yet paradoxically, lysozyme is important for the resolution of inflammation at mucosal sites. This review will highlight recent advances in our understanding of the diverse mechanisms that bacteria use to protect themselves against lysozyme, the intriguing immunomodulatory function of lysozyme, and the relationship between these features in the context of infection.
Topics: Animals; Anti-Infective Agents; Bacteria; Bacterial Infections; Humans; Immune System Phenomena; Muramidase; Peptidoglycan
PubMed: 28934357
DOI: 10.1371/journal.ppat.1006512 -
Microbiology Spectrum Dec 2015Bacterial endospores possess multiple integument layers, one of which is the cortex peptidoglycan wall. The cortex is essential for the maintenance of spore core... (Review)
Review
Bacterial endospores possess multiple integument layers, one of which is the cortex peptidoglycan wall. The cortex is essential for the maintenance of spore core dehydration and dormancy and contains structural modifications that differentiate it from vegetative cell peptidoglycan and determine its fate during spore germination. Following the engulfment stage of sporulation, the cortex is synthesized within the intermembrane space surrounding the forespore. Proteins responsible for cortex synthesis are produced in both the forespore and mother cell compartments. While some of these proteins also contribute to vegetative cell wall synthesis, others are sporulation specific. In order for the bacterial endospore to germinate and resume metabolism, the cortex peptidoglycan must first be degraded through the action of germination-specific lytic enzymes. These enzymes are present, yet inactive, in the dormant spore and recognize the muramic-δ-lactam modification present in the cortex. Germination-specific lytic enzymes across Bacillaceae and Clostridiaceae share this specificity determinant, which ensures that the spore cortex is hydrolyzed while the vegetative cell wall remains unharmed. Bacillus species tend to possess two redundant enzymes, SleB and CwlJ, capable of sufficient cortex degradation, while the clostridia have only one, SleC. Additional enzymes are often present that cannot initiate the cortex degradation process, but which can increase the rate of release of small fragments into the medium. Between the two families, the enzymes also differ in the enzymatic activities they possess and the mechanisms acting to restrict their activation until germination has been initiated.
Topics: Bacteria; Bacterial Proteins; Cell Wall; Peptidoglycan; Spores, Bacterial
PubMed: 27337277
DOI: 10.1128/microbiolspec.TBS-0005-2012 -
Biochemistry Jul 2017Cellular mechanical properties play an integral role in bacterial survival and adaptation. Historically, the bacterial cell wall and, in particular, the layer of... (Review)
Review
Cellular mechanical properties play an integral role in bacterial survival and adaptation. Historically, the bacterial cell wall and, in particular, the layer of polymeric material called the peptidoglycan were the elements to which cell mechanics could be primarily attributed. Disrupting the biochemical machinery that assembles the peptidoglycan (e.g., using the β-lactam family of antibiotics) alters the structure of this material, leads to mechanical defects, and results in cell lysis. Decades after the discovery of peptidoglycan-synthesizing enzymes, the mechanisms that underlie their positioning and regulation are still not entirely understood. In addition, recent evidence suggests a diverse group of other biochemical elements influence bacterial cell mechanics, may be regulated by new cellular mechanisms, and may be triggered in different environmental contexts to enable cell adaptation and survival. This review summarizes the contributions that different biomolecular components of the cell wall (e.g., lipopolysaccharides, wall and lipoteichoic acids, lipid bilayers, peptidoglycan, and proteins) make to Gram-negative and Gram-positive bacterial cell mechanics. We discuss the contribution of individual proteins and macromolecular complexes in cell mechanics and the tools that make it possible to quantitatively decipher the biochemical machinery that contributes to bacterial cell mechanics. Advances in this area may provide insight into new biology and influence the development of antibacterial chemotherapies.
Topics: Adaptation, Physiological; Cell Membrane; Cell Wall; Gram-Negative Bacteria; Gram-Positive Bacteria; Lipid Bilayers; Lipopolysaccharides; Microbial Viability; Peptidoglycan; Teichoic Acids
PubMed: 28666084
DOI: 10.1021/acs.biochem.7b00346 -
Nature Mar 2023Gram-negative bacteria surround their cytoplasmic membrane with a peptidoglycan (PG) cell wall and an outer membrane (OM) with an outer leaflet composed of...
Gram-negative bacteria surround their cytoplasmic membrane with a peptidoglycan (PG) cell wall and an outer membrane (OM) with an outer leaflet composed of lipopolysaccharide (LPS). This complex envelope presents a formidable barrier to drug entry and is a major determinant of the intrinsic antibiotic resistance of these organisms. The biogenesis pathways that build the surface are also targets of many of our most effective antibacterial therapies. Understanding the molecular mechanisms underlying the assembly of the Gram-negative envelope therefore promises to aid the development of new treatments effective against the growing problem of drug-resistant infections. Although the individual pathways for PG and OM synthesis and assembly are well characterized, almost nothing is known about how the biogenesis of these essential surface layers is coordinated. Here we report the discovery of a regulatory interaction between the committed enzymes for the PG and LPS synthesis pathways in the Gram-negative pathogen Pseudomonas aeruginosa. We show that the PG synthesis enzyme MurA interacts directly and specifically with the LPS synthesis enzyme LpxC. Moreover, MurA was shown to stimulate LpxC activity in cells and in a purified system. Our results support a model in which the assembly of the PG and OM layers in many proteobacterial species is coordinated by linking the activities of the committed enzymes in their respective synthesis pathways.
Topics: Cell Wall; Lipopolysaccharides; Bacterial Outer Membrane; Pseudomonas aeruginosa; Peptidoglycan
PubMed: 36859542
DOI: 10.1038/s41586-023-05750-0 -
Nature Jun 2022Linkages between the outer membrane of Gram-negative bacteria and the peptidoglycan layer are crucial for the maintenance of cellular integrity and enable survival in...
Linkages between the outer membrane of Gram-negative bacteria and the peptidoglycan layer are crucial for the maintenance of cellular integrity and enable survival in challenging environments. The function of the outer membrane is dependent on outer membrane proteins (OMPs), which are inserted into the membrane by the β-barrel assembly machine (BAM). Growing Escherichia coli cells segregate old OMPs towards the poles by a process known as binary partitioning, the basis of which is unknown. Here we demonstrate that peptidoglycan underpins the spatiotemporal organization of OMPs. Mature, tetrapeptide-rich peptidoglycan binds to BAM components and suppresses OMP foldase activity. Nascent peptidoglycan, which is enriched in pentapeptides and concentrated at septa, associates with BAM poorly and has little effect on its activity, leading to preferential insertion of OMPs at division sites. The synchronization of OMP biogenesis with cell wall growth results in the binary partitioning of OMPs as cells divide. Our study reveals that Gram-negative bacteria coordinate the assembly of two major cell envelope layers by rendering OMP biogenesis responsive to peptidoglycan maturation, a potential vulnerability that could be exploited in future antibiotic design.
Topics: Bacterial Outer Membrane Proteins; Cell Membrane; Cell Wall; Escherichia coli; Escherichia coli Proteins; Peptidoglycan; Protein Folding
PubMed: 35705811
DOI: 10.1038/s41586-022-04834-7 -
Annual Review of Biochemistry Jun 2018Peptidoglycan is an essential component of the cell wall that protects bacteria from environmental stress. A carefully coordinated biosynthesis of peptidoglycan during... (Review)
Review
Peptidoglycan is an essential component of the cell wall that protects bacteria from environmental stress. A carefully coordinated biosynthesis of peptidoglycan during cell elongation and division is required for cell viability. This biosynthesis involves sophisticated enzyme machineries that dynamically synthesize, remodel, and degrade peptidoglycan. However, when and where bacteria build peptidoglycan, and how this is coordinated with cell growth, have been long-standing questions in the field. The improvement of microscopy techniques has provided powerful approaches to study peptidoglycan biosynthesis with high spatiotemporal resolution. Recent development of molecular probes further accelerated the growth of the field, which has advanced our knowledge of peptidoglycan biosynthesis dynamics and mechanisms. Here, we review the technologies for imaging the bacterial cell wall and its biosynthesis activity. We focus on the applications of fluorescent d-amino acids, a newly developed type of probe, to visualize and study peptidoglycan synthesis and dynamics, and we provide direction for prospective research.
Topics: Amino Acids; Bacteria; Cell Wall; Fluorescent Dyes; Microscopy, Atomic Force; Microscopy, Electron; Microscopy, Fluorescence; Peptidoglycan
PubMed: 29596002
DOI: 10.1146/annurev-biochem-062917-012921 -
Molecular Microbiology Jan 2018Peptidoglycan is the predominant stress-bearing structure in the cell envelope of most bacteria, and also a potent stimulator of the eukaryotic immune system. Obligate... (Comparative Study)
Comparative Study Review
Peptidoglycan is the predominant stress-bearing structure in the cell envelope of most bacteria, and also a potent stimulator of the eukaryotic immune system. Obligate intracellular bacteria replicate exclusively within the interior of living cells, an osmotically protected niche. Under these conditions peptidoglycan is not necessarily needed to maintain the integrity of the bacterial cell. Moreover, the presence of peptidoglycan puts bacteria at risk of detection and destruction by host peptidoglycan recognition factors and downstream effectors. This has resulted in a selective pressure and opportunity to reduce the levels of peptidoglycan. In this review we have analysed the occurrence of genes involved in peptidoglycan metabolism across the major obligate intracellular bacterial species. From this comparative analysis, we have identified a group of predicted 'peptidoglycan-intermediate' organisms that includes the Chlamydiae, Orientia tsutsugamushi, Wolbachia and Anaplasma marginale. This grouping is likely to reflect biological differences in their infection cycle compared with peptidoglycan-negative obligate intracellular bacteria such as Ehrlichia and Anaplasma phagocytophilum, as well as obligate intracellular bacteria with classical peptidoglycan such as Coxiella, Buchnera and members of the Rickettsia genus. The signature gene set of the peptidoglycan-intermediate group reveals insights into minimal enzymatic requirements for building a peptidoglycan-like sacculus and/or division septum.
Topics: Anaplasma marginale; Animals; Bacteria; Cell Wall; Chlamydia; Cytoplasm; Genome, Bacterial; Host Microbial Interactions; Humans; Immunity, Innate; Intracellular Space; Orientia tsutsugamushi; Peptidoglycan; Phylogeny; Wolbachia
PubMed: 29178391
DOI: 10.1111/mmi.13880