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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 -
Angewandte Chemie (International Ed. in... Apr 2024Peptidoglycan, an essential component within the cell walls of virtually all bacteria, is composed of glycan strands linked by stem peptides that contain D-amino acids.... (Review)
Review
Peptidoglycan, an essential component within the cell walls of virtually all bacteria, is composed of glycan strands linked by stem peptides that contain D-amino acids. The peptidoglycan biosynthesis machinery exhibits high tolerance to various D-amino acid derivatives. D-amino acid derivatives with different functionalities can thus be specifically incorporated into and label the peptidoglycan of bacteria, but not the host mammalian cells. This metabolic labeling strategy is highly selective, highly biocompatible, and broadly applicable, which has been utilized in various fields. This review introduces the metabolic labeling strategies of peptidoglycan by using D-amino acid derivatives, including one-step and two-step strategies. In addition, we emphasize the various applications of D-amino acid derivative-based metabolic labeling, including bacterial peptidoglycan visualization (existence, biosynthesis, and dynamics, etc.), bacterial visualization (including bacterial imaging and visualization of growth and division, metabolic activity, antibiotic susceptibility, etc.), pathogenic bacteria-targeted diagnostics and treatment (positron emission tomography (PET) imaging, photodynamic therapy, photothermal therapy, gas therapy, immunotherapy, etc.), and live bacteria-based therapy. Finally, a summary of this metabolic labeling and an outlook is provided.
Topics: Peptidoglycan; Bacteria; Amino Acids; Cell Wall
PubMed: 38284300
DOI: 10.1002/anie.202319400 -
Current Opinion in Pharmacology Oct 2019Mounting evidence indicates that gut microbiota exerts a broad range of effects on host physiology and development beyond the gastrointestinal tract, including the... (Review)
Review
Mounting evidence indicates that gut microbiota exerts a broad range of effects on host physiology and development beyond the gastrointestinal tract, including the modulation of brain development. However, the mechanisms mediating the interactions between the microbiota and the developing brain are still poorly understood. Pattern recognition receptors of the innate immune system that recognize microbial products, such as peptidoglycans have emerged as potential key regulators of gut microbiome-brain interactions. Peptidoglycan-sensing molecules are expressed in the placenta and brain during specific time windows of development. Moreover, peptidoglycans are ubiquitously present in circulation and can cross the blood brain barrier. This review brings together the current evidence supporting a broad function of peptidoglycans well beyond host's immunity, extending to neurodevelopment and behavior.
Topics: Animals; Bacteria; Brain; Humans; Microbiota; Peptidoglycan
PubMed: 31557694
DOI: 10.1016/j.coph.2019.08.003 -
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 -
Biochemistry Apr 2023Some bacteria survive in nutrient-poor environments and resist killing by antimicrobials by forming spores. The cortex layer of the peptidoglycan cell wall that...
Some bacteria survive in nutrient-poor environments and resist killing by antimicrobials by forming spores. The cortex layer of the peptidoglycan cell wall that surrounds mature spores contains a unique modification, muramic-δ-lactam, that is essential for spore germination and outgrowth. Two proteins, the amidase CwlD and the deacetylase PdaA, are required for muramic-δ-lactam synthesis in cells, but their combined ability to generate muramic-δ-lactam has not been directly demonstrated. Here we report an in vitro reconstitution of cortex peptidoglycan biosynthesis, and we show that CwlD and PdaA together are sufficient for muramic-δ-lactam formation. Our method enables characterization of the individual reaction steps, and we show for the first time that PdaA has transamidase activity, catalyzing both the deacetylation of -acetylmuramic acid and cyclization of the product to form muramic-δ-lactam. This activity is unique among peptidoglycan deacetylases and is notable because it may involve the direct ligation of a carboxylic acid with a primary amine. Our reconstitution products are nearly identical to the cortex peptidoglycan found in spores, and we expect that they will be useful substrates for future studies of enzymes that act on the spore cortex.
Topics: Spores, Bacterial; Peptidoglycan; Bacteria; Cell Wall; Lactams; Bacterial Proteins
PubMed: 37021938
DOI: 10.1021/acs.biochem.3c00100 -
Current Opinion in Microbiology Apr 2021Peptidoglycan (PG) has remained for decades in the spotlight of the never-ending battle against pathogenic bacteria as this essential bacterial structure is one of the... (Review)
Review
Peptidoglycan (PG) has remained for decades in the spotlight of the never-ending battle against pathogenic bacteria as this essential bacterial structure is one of the most successful targets for antibiotics. Most of our current understanding about the composition, architecture, and dynamics of the PG relies on techniques which have experienced great technological and methodological improvements in the past years. Here we summarize recent advances in these methods with the intention to furnish a valuable resource for both PG experts and newcomers.
Topics: Anti-Bacterial Agents; Bacteria; Bacterial Proteins; Cell Wall; Peptidoglycan
PubMed: 33631455
DOI: 10.1016/j.mib.2021.01.010 -
Chembiochem : a European Journal of... Jun 2023The O-acetylation of the muramic acid residues in peptidoglycan (PG) is a modification that protects the bacteria from lysis due to the action of lysozyme. In...
The O-acetylation of the muramic acid residues in peptidoglycan (PG) is a modification that protects the bacteria from lysis due to the action of lysozyme. In Gram-negative bacteria, deacetylation is required to allow lytic transglycosylases to promote PG cleavage during cell growth and division. This deacetylation is catalyzed by O-acetylpeptidoglycan esterase (Ape) which is a serine esterase and employs covalent catalysis via a serine-linked acyl enzyme intermediate. Loss of Ape activity affects the size and shape of bacteria and dramatically reduces virulence. In this work, we report the first rationally designed aldehyde-based inhibitors of Ape from Campylobacter jejuni. The most potent of these acts as a competitive inhibitor with a K value of 13 μM. We suspect that the inhibitors are forming adducts with the active site serine that closely mimic the tetrahedral intermediate of the normal catalytic cycle. Support for this notion is found in the observation that reduction of the aldehyde to an alcohol effectively abolishes the inhibition.
Topics: Animals; Acetylesterase; Peptidoglycan; Aldehydes; Esterases; Bacteria; Serine; Hominidae
PubMed: 37069132
DOI: 10.1002/cbic.202300205 -
Trends in Microbiology Jun 2015Polar growth represents a surprising departure from the canonical dispersed cell growth model. However, we know relatively little of the underlying mechanisms governing... (Review)
Review
Polar growth represents a surprising departure from the canonical dispersed cell growth model. However, we know relatively little of the underlying mechanisms governing polar growth or the requisite suite of factors that direct polar growth. Underscoring how classic doctrine can be turned on its head, the peptidoglycan layer of polar-growing bacteria features unusual crosslinks and in some species the quintessential cell division proteins FtsA and FtsZ are recruited to the growing poles. Remarkably, numerous medically important pathogens utilize polar growth, accentuating the need for intensive research in this area. Here we review models of polar growth in bacteria based on recent research in the Actinomycetales and Rhizobiales, with emphasis on Mycobacterium and Agrobacterium species.
Topics: Actinomycetales; Agrobacterium; Alphaproteobacteria; Bacteria; Bacterial Proteins; Cell Cycle; Cell Division; Cytoskeletal Proteins; Mycobacterium; Peptidoglycan
PubMed: 25662291
DOI: 10.1016/j.tim.2015.01.003 -
Bioscience, Biotechnology, and... May 2024In bacteria, d-amino acids are primarily synthesized from l-amino acids by amino acid racemases, but some bacteria use d-amino acid aminotransferases to synthesize... (Review)
Review
In bacteria, d-amino acids are primarily synthesized from l-amino acids by amino acid racemases, but some bacteria use d-amino acid aminotransferases to synthesize d-amino acids. d-Amino acids are peptidoglycan components in the cell wall involved in several physiological processes, such as bacterial growth, biofilm dispersal, and peptidoglycan metabolism. Therefore, their metabolism and physiological roles have attracted increasing attention. Recently, we identified novel bacterial d-amino acid metabolic pathways, which involve amino acid racemases, with broad substrate specificity, as well as multifunctional enzymes with d-amino acid-metabolizing activity. Here, I review these multifunctional enzymes and their related d- and l-amino acid metabolic pathways in Escherichia coli and the hyperthermophile Thermotoga maritima.
Topics: Amino Acids; Thermotoga maritima; Escherichia coli; Substrate Specificity; Amino Acid Isomerases; Peptidoglycan; Transaminases; Bacterial Proteins
PubMed: 38439669
DOI: 10.1093/bbb/zbae027 -
Current Biology : CB Oct 2020A peptidoglycan (PG) cell wall is an essential component of nearly all bacteria, providing protection against turgor pressure. Metabolism of this PG meshwork must be... (Review)
Review
A peptidoglycan (PG) cell wall is an essential component of nearly all bacteria, providing protection against turgor pressure. Metabolism of this PG meshwork must be spatially and temporally regulated in order to support cell growth and division. Despite being an active area of research for decades, we have only recently identified the primary PG synthesis complexes that function during cell elongation (RodA-PBP2) and cell division (FtsW-FtsI), and we are still uncovering the importance of the other seemingly redundant cell wall enzymes. In this minireview, we highlight the discovery of the monofunctional glycosyltransferases RodA and FtsW and describe how these findings have prompted a re-evaluation of the auxiliary role of the bifunctional class A penicillin-binding proteins (aPBPs) as well as the L,D-transpeptidases (LDTs). Specifically, recent work indicates that the aPBPs and LDTs function independently of the primary morphogenetic complexes to support growth, provide protection from stresses, mediate morphogenesis, and/or allow adaptation to different growth conditions. These paradigm-shifting studies have reframed our understanding of bacterial cell wall metabolism, which will only become more refined as emerging technology allows us to tackle the remaining questions surrounding PG biosynthesis.
Topics: Bacteria; Bacterial Proteins; Cell Cycle; Cell Division; Cell Wall; Glycosyltransferases; Membrane Proteins; Penicillin-Binding Proteins; Peptidoglycan
PubMed: 33022262
DOI: 10.1016/j.cub.2020.07.004