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Molecular Microbiology Mar 2020The peptidoglycan (PG), as the exoskeleton of most prokaryotes, maintains a defined shape and ensures cell integrity against the high internal turgor pressure. These... (Review)
Review
The peptidoglycan (PG), as the exoskeleton of most prokaryotes, maintains a defined shape and ensures cell integrity against the high internal turgor pressure. These important roles have attracted researchers to target PG metabolism in order to control bacterial infections. Most studies, however, have been performed in bacteria grown under laboratory conditions, leading to only a partial view on how the PG is synthetized in natural environments. As a case in point, PG metabolism and its regulation remain poorly understood in symbiotic and pathogenic bacteria living inside eukaryotic cells. This review focuses on the PG metabolism of intracellular bacteria, emphasizing the necessity of more in vivo studies involving the analysis of enzymes produced in the intracellular niche and the isolation of PG from bacteria residing within eukaryotic cells. The review also points to persistent infections caused by some intracellular bacterial pathogens and the extent at which the PG could contribute to establish such physiological state. Based on recent evidences, I speculate on the idea that certain structural features of the PG may facilitate attenuation of intracellular growth. Lastly, I discuss recent findings in endosymbionts supporting a cooperation between host and bacterial enzymes to assemble a mature PG.
Topics: Bacteria; Bacterial Infections; Bacterial Proteins; Cell Wall; Eukaryotic Cells; Host-Pathogen Interactions; Humans; Peptidoglycan; Symbiosis; Virulence
PubMed: 32185832
DOI: 10.1111/mmi.14452 -
International Journal of Medical... Feb 2015Most Eubacteria possess peptidoglycan (PGN) or murein that surrounds the cytoplasmic membrane. While on the one hand this PGN sacculus is a very protective shield that... (Review)
Review
Most Eubacteria possess peptidoglycan (PGN) or murein that surrounds the cytoplasmic membrane. While on the one hand this PGN sacculus is a very protective shield that provides resistance to the internal turgor and adverse effects of the environment, it serves on the other hand as a major pattern of recognition due to its unique structure. Eukaryotes harness this particular bacterial macromolecule to perceive (pathogenic) microorganisms and initiate their immune defence. PGN fragments are generated by bacteria as turnover products during bacterial cell wall growth and these fragments can be sensed by plants and animals to assess a potential bacterial threat. To increase the sensitivity the concentration of PGN fragments can be amplified by host hydrolytic enzymes such as lysozyme or amidase. But also bacteria themselves are able to perceive information about the state of their cell wall by sensing small soluble fragments released from its PGN, which eventually leads to the induction of antibiotic responses or cell differentiation. How PGN is sensed by bacteria, plants and animals, and how the antibacterial defence is modulated by PGN perception is the issue of this review.
Topics: Animals; Bacteria; Bacterial Physiological Phenomena; Cell Wall; Host-Pathogen Interactions; Peptidoglycan; Plants; Receptors, Immunologic
PubMed: 25596887
DOI: 10.1016/j.ijmm.2014.12.019 -
International Journal of Medical... Sep 2019Peptidoglycan (PG) is a bacteria specific cell surface layer that ensures the bacterial shape and integrity. The two actinomycetes Amycolatopsis balhimycina and... (Review)
Review
Peptidoglycan (PG) is a bacteria specific cell surface layer that ensures the bacterial shape and integrity. The two actinomycetes Amycolatopsis balhimycina and Microbispora sp. PTA-5024 are producers of PG targeting antibiotics. To prevent the binding of their secreted product to their own PG, they developed specific self-resistance mechanisms. Modifications of PG, which are applied by both strains, are the introduction of amide-residues at the PG precursors and the alternative crosslinks within the nascent PG. The PG modifications found in Microbispora sp. PTA-5024 seemed to be an intrinsic characteristic of the genus Microbispora, rather than a specific mechanism of NAI-107 resistance. In contrast, the modifications in A. balhimycina represent an alternative way to avoid suicide specific for glycopeptide producers. The different PG modifications reflect the fact that antibiotic producing organisms contain not only one but multiple mechanisms to ensure protection against biologically active molecules produced by themselves.
Topics: Actinobacteria; Amino Acids; Anti-Bacterial Agents; Bacterial Proteins; Drug Resistance, Bacterial; Glycopeptides; Peptidoglycan; Polymerization
PubMed: 31350128
DOI: 10.1016/j.ijmm.2019.151332 -
Chemistry (Weinheim An Der Bergstrasse,... Feb 2018The cell wall envelope of mycobacteria is structurally distinct from that of both Gram-positive and Gram-negative bacteria. In Mycobacterium tuberculosis, this cell wall... (Review)
Review
The cell wall envelope of mycobacteria is structurally distinct from that of both Gram-positive and Gram-negative bacteria. In Mycobacterium tuberculosis, this cell wall has unique structural features and plays a crucial role in drug resistance and macrophage survival under stress conditions. Peptidoglycan is the major constituent of this cell wall, with an important structural role, giving structural strength, and counteracting the osmotic pressure of the cytoplasm. Synthesis of this complex polymer takes place in three stages that occur at three different locations in the cell, from the cytoplasm to the external side of the cell membrane, where polymerization occurs. A fine balance of peptidoglycan synthesis and degradation is responsible for a plethora of molecular mechanisms which are key to the pathogenicity of M. tuberculosis. Enlargement of mycobacterial cells can occur through the synthesis of new peptidoglycan, autolysis of old peptidoglycan, or a combination of both processes. Here, we discuss the chemical aspects of peptidoglycan synthesis and degradation, in relation to metabolic stages of M. tuberculosis. Going from inside the mycobacterial cytoplasm to outside its membrane, we describe the assembly line of peptidoglycan synthesis and polymerization, and continue with its depolymerization events and their consequences on mycobacterial life and resuscitation from dormancy.
Topics: Alkyl and Aryl Transferases; Cell Wall; Cytoplasm; Mycobacterium tuberculosis; Peptidoglycan; Protein Structure, Tertiary
PubMed: 28925518
DOI: 10.1002/chem.201702973 -
Trends in Microbiology Feb 2010Peptidoglycan forms a net-like sacculus made of glycan strands crosslinked by peptides. The length of the glycan strands and the degree of crosslinkage vary with... (Review)
Review
Peptidoglycan forms a net-like sacculus made of glycan strands crosslinked by peptides. The length of the glycan strands and the degree of crosslinkage vary with bacterial species, strains and growth conditions. Several models for the three-dimensional architecture of peptidoglycan have been proposed, some of which have been tested experimentally. The new data support a layered model in Gram-negative bacteria, and a more elaborate peptidoglycan architecture, with bands made of coiled bundles of glycan strands, in the rod-shaped Bacillus subtilis. However, many questions remain unanswered and, therefore, more data and more models are required to decipher the complex cell wall architecture in bacteria.
Topics: Cell Wall; Gram-Negative Bacteria; Gram-Positive Bacteria; Models, Biological; Models, Chemical; Peptidoglycan
PubMed: 20060721
DOI: 10.1016/j.tim.2009.12.004 -
Chembiochem : a European Journal of... Apr 2023Serving as an exoskeletal scaffold, peptidoglycan is a polymeric macromolecule that is essential and conserved across all bacteria, yet is absent in mammalian cells;... (Review)
Review
Serving as an exoskeletal scaffold, peptidoglycan is a polymeric macromolecule that is essential and conserved across all bacteria, yet is absent in mammalian cells; this has made bacterial peptidoglycan a well-established excellent antibiotic target. In addition, soluble peptidoglycan fragments derived from bacteria are increasingly recognised as key signalling molecules in mediating diverse intra- and inter-species communication in nature, including in gut microbiota-host crosstalk. Each bacterial species encodes multiple redundant enzymes for key enzymatic activities involved in peptidoglycan assembly and breakdown. In this review, we discuss recent findings on the biochemical activities of major peptidoglycan enzymes, including peptidoglycan glycosyltransferases (PGT) and transpeptidases (TPs) in the final stage of peptidoglycan assembly, as well as peptidoglycan glycosidases, lytic transglycosylase (LTs), amidases, endopeptidases (EPs) and carboxypeptidases (CPs) in peptidoglycan turnover and metabolism. Biochemical characterisation of these enzymes provides valuable insights into their substrate specificity, regulation mechanisms and potential modes of inhibition.
Topics: Peptidoglycan; Bacteria; Glycosyltransferases; Cell Wall; Substrate Specificity; Bacterial Proteins
PubMed: 36715567
DOI: 10.1002/cbic.202200693 -
Current Opinion in Microbiology Feb 2005Bacterial pathogens rely on a variety of virulence factors to establish the colonization of a new niche. Although peptidoglycan and its muropeptide derivatives have been... (Review)
Review
Bacterial pathogens rely on a variety of virulence factors to establish the colonization of a new niche. Although peptidoglycan and its muropeptide derivatives have been known to possess potent biological properties, until recently the molecular bases were poorly understood. With the identification of the cytosolic surveillance mechanism mediated by the nucleotide-binding oligomerization domain (Nod)1 and Nod2 proteins, which detect unique peptidoglycan-derived muropeptides, these muropeptides should be considered as potential virulence factors. Recent research highlights the role of peptidoglycan in the pathogenesis of different human pathogens such as Streptococcus pneumoniae, Listeria monocytogenes or Helicobacter pylori.
Topics: Adaptor Proteins, Signal Transducing; Animals; Bacteria; Bacterial Infections; Guinea Pigs; Helicobacter pylori; Humans; Listeria monocytogenes; Mice; Peptidoglycan; Rats; Virulence
PubMed: 15694856
DOI: 10.1016/j.mib.2004.12.008 -
Bioorganic Chemistry Jun 2014Post-synthetic modification of the bacterial cell wall represents an important strategy for pathogenic bacteria to evade innate immunity and control autolysins.... (Review)
Review
Post-synthetic modification of the bacterial cell wall represents an important strategy for pathogenic bacteria to evade innate immunity and control autolysins. Modifications to the glycan backbone of peptidoglycan are generally restricted to the C-6 hydroxyl and C-3 amino moieties, with the most common being acetylation and deacetylation. In this review we discuss the pathways for O-acetylation, de-O-acetylation and N-deacetylation with an emphasis on the chemical-biological approaches used in their investigation. The current challenges in the field and the prospects of targeting these systems with novel therapeutics are also explored.
Topics: Acetylation; Models, Molecular; Molecular Structure; Peptidoglycan
PubMed: 24769153
DOI: 10.1016/j.bioorg.2014.03.010 -
Bioorganic Chemistry Aug 2014The widespread emergence of resistant bacterial strains is becoming a serious threat to public health. This thus signifies the need for the development of new... (Review)
Review
The widespread emergence of resistant bacterial strains is becoming a serious threat to public health. This thus signifies the need for the development of new antibacterial agents with novel mechanisms of action. Continuous efforts in the design of novel antibacterials remain one of the biggest challenges in drug development. In this respect, the Mur enzymes, MurA-F, that are involved in the formation of UDP-N-acetylmuramyl-pentapeptide can be genuinely considered as promising antibacterial targets. This review provides an in-depth insight into the recent developments in the field of inhibitors of the MurA-F enzymes. Special attention is also given to compounds that act as multiple inhibitors of two, three or more of the Mur enzymes. Moreover, the reasons for the lack of preclinically successful inhibitors and the challenges to overcome these hurdles in the next years are also debated.
Topics: Alkyl and Aryl Transferases; Animals; Enzyme Inhibitors; Humans; Peptidoglycan
PubMed: 24755374
DOI: 10.1016/j.bioorg.2014.03.008 -
PLoS Pathogens Jan 2022Salmonella enterica causes intracellular infections that can be limited to the intestine or spread to deeper tissues. In most cases, intracellular bacteria show moderate...
Salmonella enterica causes intracellular infections that can be limited to the intestine or spread to deeper tissues. In most cases, intracellular bacteria show moderate growth. How these bacteria face host defenses that recognize peptidoglycan, is poorly understood. Here, we report a high-resolution structural analysis of the minute amounts of peptidoglycan purified from S. enterica serovar Typhimurium (S. Typhimurium) infecting fibroblasts, a cell type in which this pathogen undergoes moderate growth and persists for days intracellularly. The peptidoglycan of these non-proliferating bacteria contains atypical crosslinked muropeptides with stem peptides trimmed at the L-alanine-D-glutamic acid-(γ) or D-glutamic acid-(γ)-meso-diaminopimelic acid motifs, both sensed by intracellular immune receptors. This peptidoglycan has a reduced glycan chain average length and ~30% increase in the L,D-crosslink, a type of bridge shared by all the atypical crosslinked muropeptides identified. The L,D-transpeptidases LdtD (YcbB) and LdtE (YnhG) are responsible for the formation of these L,D-bridges in the peptidoglycan of intracellular bacteria. We also identified in a fraction of muropeptides an unprecedented modification in the peptidoglycan of intracellular S. Typhimurium consisting of the amino alcohol alaninol replacing the terminal (fourth) D-alanine. Alaninol was still detectable in the peptidoglycan of a double mutant lacking LdtD and LdtE, thereby ruling out the contribution of these enzymes to this chemical modification. Remarkably, all multiple mutants tested lacking candidate enzymes that either trim stem peptides or form the L,D-bridges retain the capacity to modify the terminal D-alanine to alaninol and all attenuate NF-κB nuclear translocation. These data inferred a potential role of alaninol-containing muropeptides in attenuating pro-inflammatory signaling, which was confirmed with a synthetic tetrapeptide bearing such amino alcohol. We suggest that the modification of D-alanine to alaninol in the peptidoglycan of non-proliferating intracellular S. Typhimurium is an editing process exploited by this pathogen to evade immune recognition inside host cells.
Topics: Cell Line; Cell Wall; Humans; Immune Tolerance; Peptidoglycan; Salmonella Infections; Salmonella enterica
PubMed: 35077524
DOI: 10.1371/journal.ppat.1010241