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Microbiology Spectrum Aug 2014The complex cell envelope is a hallmark of mycobacteria and is anchored by the peptidoglycan layer, which is similar to that of Escherichia coli and a number of other... (Review)
Review
The complex cell envelope is a hallmark of mycobacteria and is anchored by the peptidoglycan layer, which is similar to that of Escherichia coli and a number of other bacteria but with modifications to the monomeric units and other structural complexities that are likely related to a role for the peptidoglycan in stabilizing the mycolyl-arabinogalactan-peptidoglycan complex (MAPc). In this article, we will review the genetics of several aspects of peptidoglycan biosynthesis in mycobacteria, including the production of monomeric precursors in the cytoplasm, assembly of the monomers into the mature wall, cell wall turnover, and cell division. Finally, we will touch upon the resistance of mycobacteria to β-lactam antibiotics, an important class of drugs that, until recently, have not been extensively exploited as potential antimycobacterial agents. We will also note areas of research where there are still unanswered questions.
Topics: Anti-Bacterial Agents; Biosynthetic Pathways; Mycobacterium; Peptidoglycan; beta-Lactams
PubMed: 26104213
DOI: 10.1128/microbiolspec.MGM2-0034-2013 -
ELife May 2020Profiling the phenotype of 200,000 mutants revealed a new cofactor that may help a group of rod-shaped bacteria elongate and grow.
Profiling the phenotype of 200,000 mutants revealed a new cofactor that may help a group of rod-shaped bacteria elongate and grow.
Topics: Bacteria; Cell Wall; Peptidoglycan; Phenotype
PubMed: 32379045
DOI: 10.7554/eLife.57043 -
Current Opinion in Microbiology Apr 2017In Gram-negative bacteria such as Escherichia coli the peptidoglycan sacculus resides in the periplasm, a compartment that experiences changes in pH value, osmolality,... (Review)
Review
In Gram-negative bacteria such as Escherichia coli the peptidoglycan sacculus resides in the periplasm, a compartment that experiences changes in pH value, osmolality, ion strength and other parameters depending on the cell's environment. Hence, the cell needs robust peptidoglycan growth mechanisms to grow and divide under different conditions. Here we propose a model according to which the cell achieves robust peptidoglycan growth by employing dynamic multi-protein complexes, which assemble with variable composition from freely diffusing sets of peptidoglycan synthases, hydrolases and their regulators, whereby the composition of the active complexes depends on the cell cycle state - cell elongation or division - and the periplasmic growth conditions.
Topics: Cell Division; Cell Wall; Escherichia coli; Gram-Negative Bacteria; Hydrolases; Models, Biological; Penicillin-Binding Proteins; Peptidoglycan; Periplasm
PubMed: 28214390
DOI: 10.1016/j.mib.2017.01.006 -
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 -
Microbiology and Molecular Biology... Dec 2018The clinical and epidemiological threat of the growing antimicrobial resistance in Gram-negative pathogens, particularly for β-lactams, the most frequently used and... (Review)
Review
The clinical and epidemiological threat of the growing antimicrobial resistance in Gram-negative pathogens, particularly for β-lactams, the most frequently used and relevant antibiotics, urges research to find new therapeutic weapons to combat the infections caused by these microorganisms. An essential previous step in the development of these therapeutic solutions is to identify their potential targets in the biology of the pathogen. This is precisely what we sought to do in this review specifically regarding the barely exploited field analyzing the interplay among the biology of the peptidoglycan and related processes, such as β-lactamase regulation and virulence. Hence, here we gather, analyze, and integrate the knowledge derived from published works that provide information on the topic, starting with those dealing with the historically neglected essential role of the Gram-negative peptidoglycan in virulence, including structural, biogenesis, remodeling, and recycling aspects, in addition to proinflammatory and other interactions with the host. We also review the complex link between intrinsic β-lactamase production and peptidoglycan metabolism, as well as the biological costs potentially associated with the expression of horizontally acquired β-lactamases. Finally, we analyze the existing evidence from multiple perspectives to provide useful clues for identifying targets enabling the future development of therapeutic options attacking the peptidoglycan-virulence interconnection as a key weak point of the Gram-negative pathogens to be used, if not to kill the bacteria, to mitigate their capacity to produce severe infections.
Topics: Animals; Anti-Bacterial Agents; Cell Wall; Gram-Negative Bacteria; Host-Pathogen Interactions; Humans; Mice; Mice, Knockout; Peptidoglycan; Virulence; beta-Lactamases
PubMed: 30209071
DOI: 10.1128/MMBR.00033-18 -
Trends in Microbiology Mar 2018Bacteria come in a wide variety of shapes and sizes. The true picture of bacterial morphological diversity is likely skewed due to an experimental focus on pathogens and... (Review)
Review
Bacteria come in a wide variety of shapes and sizes. The true picture of bacterial morphological diversity is likely skewed due to an experimental focus on pathogens and industrially relevant organisms. Indeed, most of the work elucidating the genes and molecular processes involved in maintaining bacterial morphology has been limited to rod- or coccal-shaped model systems. The mechanisms of shape evolution, the molecular processes underlying diverse shapes and growth modes, and how individual cells can dynamically modulate their shape are just beginning to be revealed. Here we discuss recent work aimed at advancing our knowledge of shape diversity and uncovering the molecular basis for shape generation in noncanonical and morphologically complex bacteria.
Topics: Bacteria; Bacterial Physiological Phenomena; Biological Evolution; Cell Plasticity; Cell Wall; Models, Biological; Peptidoglycan; Species Specificity
PubMed: 29056293
DOI: 10.1016/j.tim.2017.09.012 -
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 -
The FEBS Journal Mar 2017During growth and propagation, a bacterial cell enlarges and subsequently divides its peptidoglycan (PG) sacculus, a continuous mesh-like layer that encases the cell... (Review)
Review
During growth and propagation, a bacterial cell enlarges and subsequently divides its peptidoglycan (PG) sacculus, a continuous mesh-like layer that encases the cell membrane to confer mechanical strength and morphological robustness. The mechanism of sacculus growth, how it is regulated and how it is coordinated with other cellular processes is poorly understood. In this article, we will discuss briefly the current knowledge of how cell wall synthesis is regulated, on multiple levels, from both sides of the cytoplasmic membrane. According to the current knowledge, cytosolic scaffolding proteins connect PG synthases with cytoskeletal elements, and protein phosphorylation regulates cell wall growth in Gram-positive species. PG-active enzymes engage in multiple protein-protein interactions within PG synthesis multienzyme complexes, and some of the interactions modulate activities. PG synthesis is also regulated by central metabolism, and by PG maturation through the action of PG hydrolytic enzymes. Only now are we beginning to appreciate how these multiple levels of regulating PG synthesis enable the cell to propagate robustly with a defined cell shape under different and variable growth conditions.
Topics: Cell Membrane; Cell Wall; Cytoskeleton; Escherichia coli; Multienzyme Complexes; Peptidoglycan; Protein Interaction Maps
PubMed: 27862967
DOI: 10.1111/febs.13959 -
Philosophical Transactions of the Royal... Oct 2015Peptidoglycan (PG) is an essential component in the cell wall of nearly all bacteria, forming a continuous, mesh-like structure, called the sacculus, around the... (Review)
Review
Peptidoglycan (PG) is an essential component in the cell wall of nearly all bacteria, forming a continuous, mesh-like structure, called the sacculus, around the cytoplasmic membrane to protect the cell from bursting by its turgor. Although PG synthases, the penicillin-binding proteins (PBPs), have been studied for 70 years, useful in vitro assays for measuring their activities were established only recently, and these provided the first insights into the regulation of these enzymes. Here, we review the current knowledge on the glycosyltransferase and transpeptidase activities of PG synthases. We provide new data showing that the bifunctional PBP1A and PBP1B from Escherichia coli are active upon reconstitution into the membrane environment of proteoliposomes, and that these enzymes also exhibit DD-carboxypeptidase activity in certain conditions. Both novel features are relevant for their functioning within the cell. We also review recent data on the impact of protein-protein interactions and other factors on the activities of PBPs. As an example, we demonstrate a synergistic effect of multiple protein-protein interactions on the glycosyltransferase activity of PBP1B, by its cognate lipoprotein activator LpoB and the essential cell division protein FtsN.
Topics: Escherichia coli; Escherichia coli Proteins; Kinetics; Models, Molecular; Penicillin-Binding Proteins; Peptidoglycan; Peptidoglycan Glycosyltransferase; Substrate Specificity
PubMed: 26370943
DOI: 10.1098/rstb.2015.0031 -
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