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International Journal of Molecular... Nov 2021Bacteria must maintain the ability to modify and repair the peptidoglycan layer without jeopardising its essential functions in cell shape, cellular integrity and... (Review)
Review
Bacteria must maintain the ability to modify and repair the peptidoglycan layer without jeopardising its essential functions in cell shape, cellular integrity and intermolecular interactions. A range of new experimental techniques is bringing an advanced understanding of how bacteria regulate and achieve peptidoglycan synthesis, particularly in respect of the central role played by complexes of Sporulation, Elongation or Division (SEDs) and class B penicillin-binding proteins required for cell division, growth and shape. In this review we highlight relationships implicated by a bioinformatic approach between the outer membrane, cytoskeletal components, periplasmic control proteins, and cell elongation/division proteins to provide further perspective on the interactions of these cell division, growth and shape complexes. We detail the network of protein interactions that assist in the formation of peptidoglycan and highlight the increasingly dynamic and connected set of protein machinery and macrostructures that assist in creating the cell envelope layers in Gram-negative bacteria.
Topics: Bacterial Proteins; Cell Membrane; Cell Wall; Gram-Negative Bacteria; Penicillin-Binding Proteins; Peptidoglycan; Periplasmic Proteins
PubMed: 34884635
DOI: 10.3390/ijms222312831 -
MBio Oct 2020Single-celled organisms must adapt their physiology to persist and propagate across a wide range of environmental conditions. The growth and division of bacterial cells... (Review)
Review
Single-celled organisms must adapt their physiology to persist and propagate across a wide range of environmental conditions. The growth and division of bacterial cells depend on continuous synthesis of an essential extracellular barrier: the peptidoglycan cell wall, a polysaccharide matrix that counteracts turgor pressure and confers cell shape. Unlike many other essential processes and structures within the bacterial cell, the peptidoglycan cell wall and its synthesis machinery reside at the cell surface and are thus uniquely vulnerable to the physicochemical environment and exogenous threats. In addition to the diversity of stressors endangering cell wall integrity, defects in peptidoglycan metabolism require rapid repair in order to prevent osmotic lysis, which can occur within minutes. Here, we review recent work that illuminates mechanisms that ensure robust peptidoglycan metabolism in response to persistent and acute environmental stress. Advances in our understanding of bacterial cell wall quality control promise to inform the development and use of antimicrobial agents that target the synthesis and remodeling of this essential macromolecule. Nearly all bacteria are encased in a peptidoglycan cell wall, an essential polysaccharide structure that protects the cell from osmotic rupture and reinforces cell shape. The integrity of this protective barrier must be maintained across the diversity of environmental conditions wherein bacteria replicate. However, at the cell surface, the cell wall and its synthesis machinery face unique challenges that threaten their integrity. Directly exposed to the extracellular environment, the peptidoglycan synthesis machinery encounters dynamic and extreme physicochemical conditions, which may impair enzymatic activity and critical protein-protein interactions. Biotic and abiotic stressors-including host defenses, cell wall active antibiotics, and predatory bacteria and phage-also jeopardize peptidoglycan integrity by introducing lesions, which must be rapidly repaired to prevent cell lysis. Here, we review recently discovered mechanisms that promote robust peptidoglycan synthesis during environmental and acute stress and highlight the opportunities and challenges for the development of cell wall active therapeutics.
Topics: Bacteria; Bacterial Proteins; Cell Membrane; Cell Wall; Peptidoglycan; Stress, Physiological
PubMed: 33051371
DOI: 10.1128/mBio.02456-20 -
Cell Chemical Biology May 2023The bacterial cell wall is composed of a highly crosslinked matrix of glycopeptide polymers known as peptidoglycan that dictates bacterial cell morphology and protects... (Review)
Review
The bacterial cell wall is composed of a highly crosslinked matrix of glycopeptide polymers known as peptidoglycan that dictates bacterial cell morphology and protects against environmental stresses. Regulation of peptidoglycan turnover is therefore crucial for bacterial survival and growth and is mediated by key protein complexes and enzyme families. Here, we review the prevalence, structure, and activity of NlpC/P60 peptidases, a family of peptidoglycan hydrolases that are crucial for cell wall turnover and division as well as interactions with antibiotics and different hosts. Understanding the molecular functions of NlpC/P60 peptidases should provide important insight into bacterial physiology, their interactions with different kingdoms of life, and the development of new therapeutic approaches.
Topics: Peptide Hydrolases; Peptidoglycan; Bacteria; Cell Wall; Bacterial Physiological Phenomena; Bacterial Proteins
PubMed: 36417916
DOI: 10.1016/j.chembiol.2022.11.001 -
Journal of Agricultural and Food... Sep 2022Lysostaphin is a potent bacteriolytic enzyme with endopeptidase activity against the common pathogen . By digesting the pentaglycine crossbridge in the cell wall... (Review)
Review
Lysostaphin is a potent bacteriolytic enzyme with endopeptidase activity against the common pathogen . By digesting the pentaglycine crossbridge in the cell wall peptidoglycan of including the methicillin-resistant strains, lysostaphin initiates rapid lysis of planktonic and sessile cells (biofilms) and has great potential for use in agriculture, food industries, and pharmaceutical industries. In the past few decades, there have been tremendous efforts in potentiating lysostaphin for better applications in these fields, including engineering of the enzyme for higher potency and lower immunogenicity with longer-lasting effects, formulation and immobilization of the enzyme for higher stability and better durability, and recombinant expression for low-cost industrial production and biocontrol. These achievements are extensively reviewed in this article focusing on applications in disease control, food preservation, surface decontamination, and pathogen detection. In addition, some basic properties of lysostaphin that have been controversial and only elucidated recently are summarized, including the substrate-binding properties, the number of zinc-binding sites, the substrate range, and the cleavage site in the pentaglycine crossbridge. Resistance to lysostaphin is also highlighted with a focus on various mechanisms. This article is concluded with a discussion on the limitations and future perspectives for the actual applications of lysostaphin.
Topics: Anti-Bacterial Agents; Bacteriolysis; Lysostaphin; Peptidoglycan; Staphylococcus aureus; Zinc
PubMed: 36082619
DOI: 10.1021/acs.jafc.2c03459 -
Current Opinion in Microbiology Apr 2024Our ability to control the growth of Gram-negative bacterial pathogens is challenged by rising antimicrobial resistance and requires new approaches. Endolysins are... (Review)
Review
Our ability to control the growth of Gram-negative bacterial pathogens is challenged by rising antimicrobial resistance and requires new approaches. Endolysins are phage-derived enzymes that degrade peptidoglycan and therefore offer potential as antimicrobial agents. However, the outer membrane (OM) of Gram-negative bacteria impedes the access of externally applied endolysins to peptidoglycan. This review highlights recent advances in the discovery and characterization of natural endolysins that can breach the OM, as well as chemical and engineering approaches that increase antimicrobial efficacy of endolysins against Gram-negative pathogens.
Topics: Anti-Bacterial Agents; Peptidoglycan; Endopeptidases; Anti-Infective Agents; Gram-Negative Bacteria; Bacteriophages
PubMed: 38350268
DOI: 10.1016/j.mib.2024.102433 -
Current Opinion in Microbiology Apr 2023Most bacteria are surrounded by a cell wall composed of peptidoglycan (PG) that specifies shape and protects the cell from osmotic rupture. Growth, division, and... (Review)
Review
Most bacteria are surrounded by a cell wall composed of peptidoglycan (PG) that specifies shape and protects the cell from osmotic rupture. Growth, division, and morphogenesis are intimately linked to the synthesis of this exoskeleton but also its hydrolysis. The enzymes that cleave the PG meshwork require careful control to prevent aberrant hydrolysis and loss of envelope integrity. Bacteria employ diverse mechanisms to control the activity, localization, and abundance of these potentially autolytic enzymes. Here, we discuss four examples of how cells integrate these control mechanisms to finely tune cell wall hydrolysis. We highlight recent advances and exciting avenues for future investigation.
Topics: Peptidoglycan; N-Acetylmuramoyl-L-alanine Amidase; Bacteria; Cell Wall; Bacterial Proteins
PubMed: 36812681
DOI: 10.1016/j.mib.2023.102279 -
Methods in Molecular Biology (Clifton,... 2024Most bacterial secretion systems are large machines that cross the cell envelope to deliver effectors outside the cell or directly into target cells. The peptidoglycan...
Most bacterial secretion systems are large machines that cross the cell envelope to deliver effectors outside the cell or directly into target cells. The peptidoglycan layer can therefore represent a physical barrier for the assembly of these large machines. Secretion systems and their counterparts such as type IV pili, flagella, and conjugation machines have therefore evolved or hijacked enzymes with peptidoglycan degradation activity. These enzymes are usually glycoside hydrolases that cleave the glycan chains of the peptidoglycan. Their activities are spatially controlled to avoid cell lysis and to create local rearrangement of the cell wall. In addition, peptidoglycan hydrolases may not be only required for the proper assembly of the secretion systems but may directly participate to the release of the effectors. Finally, several antibacterial effectors possess peptidoglycan degradation activity that damage the cell wall once delivered in the target cell. Here, we describe protocols to test the peptidoglycan degradation activity of these proteins in vitro and in solution.
Topics: Peptidoglycan; Anti-Bacterial Agents; Bacterial Secretion Systems; Cell Death; Cell Membrane
PubMed: 37930529
DOI: 10.1007/978-1-0716-3445-5_12 -
Frontiers in Cellular and Infection... 2023Most bacteria divide through a highly conserved process called binary fission, in which there is symmetric growth of daughter cells and the synthesis of peptidoglycan at... (Review)
Review
Most bacteria divide through a highly conserved process called binary fission, in which there is symmetric growth of daughter cells and the synthesis of peptidoglycan at the mid-cell to enable cytokinesis. During this process, the parental cell replicates its chromosomal DNA and segregates replicated chromosomes into the daughter cells. The mechanisms that regulate binary fission have been extensively studied in several model organisms, including , and . These analyses have revealed that a multi-protein complex called the divisome forms at the mid-cell to enable peptidoglycan synthesis and septation during division. In addition, rod-shaped bacteria form a multi-protein complex called the elongasome that drives sidewall peptidoglycan synthesis necessary for the maintenance of rod shape and the lengthening of the cell prior to division. In adapting to their intracellular niche, the obligate intracellular bacteria discussed here have eliminated one to several of the divisome gene products essential for binary fission in . In addition, genes that encode components of the elongasome, which were mostly lost as rod-shaped bacteria evolved into coccoid organisms, have been retained during the reductive evolutionary process that some coccoid obligate intracellular bacteria have undergone. Although the precise molecular mechanisms that regulate the division of obligate intracellular bacteria remain undefined, the studies summarized here indicate that obligate intracellular bacteria exhibit remarkable plasticity in their cell division processes.
Topics: Escherichia coli; Peptidoglycan; Bacterial Proteins; Cell Division; Cytokinesis
PubMed: 37876871
DOI: 10.3389/fcimb.2023.1205488 -
Proceedings of the National Academy of... Oct 2023Bacteria produce a structural layer of peptidoglycan (PG) that enforces cell shape, resists turgor pressure, and protects the cell. As bacteria grow and divide, the...
Bacteria produce a structural layer of peptidoglycan (PG) that enforces cell shape, resists turgor pressure, and protects the cell. As bacteria grow and divide, the existing layer of PG is remodeled and PG fragments are released. Enterics such as go to great lengths to internalize and reutilize PG fragments. is estimated to break down one-third of its cell wall, yet only loses ~0 to 5% of meso-diaminopimelic acid, a PG-specific amino acid, per generation. Two transporters were identified early on to possibly be the primary permease that facilitates PG fragment recycling, i) AmpG and ii) the Opp ATP binding cassette transporter in conjunction with a PG-specific periplasmic binding protein, MppA. The contribution of each transporter to PG recycling has been debated. Here, we have found that AmpG and MppA/Opp are differentially regulated by carbon source and growth phase. In addition, MppA/Opp is uniquely capable of high-affinity scavenging of muropeptides from growth media, demonstrating that AmpG and MppA/Opp allow for different strategies of recycling PG fragments. Altogether, this work clarifies environmental contexts under which utilizes distinct permeases for PG recycling and explores how scavenging by MppA/Opp could be beneficial in mixed communities.
Topics: Membrane Transport Proteins; Escherichia coli; Peptidoglycan; Bacterial Proteins; Bacteria; Cell Wall
PubMed: 37871219
DOI: 10.1073/pnas.2308940120 -
Current Opinion in Chemical Biology Aug 2020Tuberculosis killed 1.5 million people in 2018. Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is the most deadly infectious bacteria in the... (Review)
Review
Tuberculosis killed 1.5 million people in 2018. Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is the most deadly infectious bacteria in the world. A strength of mycobacterial pathogens - their formidable cell wall - could also be one of their greatest molecular vulnerabilities. As in other bacteria, peptidoglycan (PG) maintenance and integrity is essential to mycobacterial survival. But Mtb PG is unique, and a better understanding of its biosynthetic machinery could lead to new drugs or more effective treatment regimens. Such investigations are being accelerated by the application of fluorescent probes, including those based on vancomycin, β-lactams, PG stem mimics, d-amino acids, and reactive glycans. This review will describe how fluorescent probes are being used to uncover new information on the regulation and drug susceptibility of two classes of enzymes that fortify the Mtb PG: the penicillin-binding proteins and the L,D-transpeptidases.
Topics: Animals; Anti-Bacterial Agents; Biosynthetic Pathways; Fluorescent Dyes; Humans; Models, Molecular; Mycobacterium tuberculosis; Optical Imaging; Peptides; Peptidoglycan; Peptidyl Transferases; Tuberculosis; Vancomycin; beta-Lactams
PubMed: 32531742
DOI: 10.1016/j.cbpa.2020.04.006