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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 -
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 -
Frontiers in Bioscience (Scholar... Jan 2013Bacteria derive and maintain a variety of shapes that carry selective benefits. The shapes are usually defined by a mechanically stiff exoskeletal cell wall -- a... (Review)
Review
Bacteria derive and maintain a variety of shapes that carry selective benefits. The shapes are usually defined by a mechanically stiff exoskeletal cell wall -- a macro-molecular network of peptidoglycan. The growth of such a network is catalyzed by transglycosylases and transpeptidases, and various cell-wall remodeling enzymes further digest and process the network. To maintain the overall cell shape, the bacterial cytoskeleton coordinates cell wall synthesis on the cellular scale. Recent studies also suggest that the mechanical properties of the bacterial cytoskeleton are important for cell wall growth. Here, we review current experiments and theories on the structure, dynamics and interactions of the bacterial cell wall and cytoskeleton, and their contributions to cell shape maintenance. We also propose future research directions that will help clarify the mystery of bacterial cell morphogenesis.
Topics: Bacteria; Cell Shape; Cell Wall; Cytoskeleton; Peptidoglycan
PubMed: 23277069
DOI: 10.2741/s390 -
FEMS Microbiology Reviews Nov 2007Bacterial peptidoglycan amidases are a large and diverse group of enzymes. During the last few years, genomic sequence information has accumulated to an extent such that... (Review)
Review
Bacterial peptidoglycan amidases are a large and diverse group of enzymes. During the last few years, genomic sequence information has accumulated to an extent such that lists of proven or predicted peptidoglycan amidases can now be expected to be fairly complete. Moreover, representative crystal structures for most groups of phylogenetically related peptidoglycan amidases have been solved. Here, sequence and structural information is combined with published biochemical findings to demonstrate that (a) peptidoglycan amidases have evolved for almost every bond that occurs in peptidoglycan, (b) there are enzymes that share the fold, yet cleave different bonds and (c) there are enzymes that have entirely different folds and must have evolved independently, and yet cleave the same peptide bond. It is shown that despite these complications, some rules can be deduced from the available biochemical and structural information that can be useful to predict the specificity of hypothetical peptidoglycan hydrolases, for which only sequence information is available.
Topics: Amidohydrolases; Bacillus subtilis; Bacterial Physiological Phenomena; Bacterial Proteins; Escherichia coli; Peptidoglycan; Protein Structure, Tertiary; Structure-Activity Relationship
PubMed: 17888003
DOI: 10.1111/j.1574-6976.2007.00084.x -
Parasitology Feb 2018Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), is recognized as a global health emergency as promoted by the World Health Organization.... (Review)
Review
Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis (TB), is recognized as a global health emergency as promoted by the World Health Organization. Over 1 million deaths per year, along with the emergence of multi- and extensively-drug resistant strains of Mtb, have triggered intensive research into the pathogenicity and biochemistry of this microorganism, guiding the development of anti-TB chemotherapeutic agents. The essential mycobacterial cell wall, sharing some common features with all bacteria, represents an apparent 'Achilles heel' that has been targeted by TB chemotherapy since the advent of TB treatment. This complex structure composed of three distinct layers, peptidoglycan, arabinogalactan and mycolic acids, is vital in supporting cell growth, virulence and providing a barrier to antibiotics. The fundamental nature of cell wall synthesis and assembly has rendered the mycobacterial cell wall as the most widely exploited target of anti-TB drugs. This review provides an overview of the biosynthesis of the prominent cell wall components, highlighting the inhibitory mechanisms of existing clinical drugs and illustrating the potential of other unexploited enzymes as future drug targets.
Topics: Anti-Bacterial Agents; Cell Wall; Drug Delivery Systems; Drug Design; Galactans; Humans; Mycobacterium tuberculosis; Mycolic Acids; Peptidoglycan; Tuberculosis; Virulence
PubMed: 27976597
DOI: 10.1017/S0031182016002377 -
Developmental and Comparative Immunology Jan 2014Innate immunity is the front line of self-defense against infectious non-self in vertebrates and invertebrates. The innate immune system is mediated by germ-line... (Review)
Review
Innate immunity is the front line of self-defense against infectious non-self in vertebrates and invertebrates. The innate immune system is mediated by germ-line encoding pattern recognition molecules (pathogen sensors) that recognize conserved molecular patterns present in the pathogens but absent in the host. Peptidoglycans (PGN) are essential cell wall components of almost all bacteria, except mycoplasma lacking a cell wall, which provides the host immune system an advantage for detecting invading bacteria. Several families of pattern recognition molecules that detect PGN and PGN-derived compounds have been indentified, and the role of PGRP family members in host defense is relatively well-characterized in Drosophila. This review focuses on the role of PGRP family members in the recognition of invading bacteria and the activation and modulation of immune responses in Drosophila.
Topics: Animals; Bacterial Infections; Cell Wall; Drosophila Proteins; Drosophila melanogaster; Host-Pathogen Interactions; Humans; Immunity, Innate; Peptidoglycan; Receptors, Pattern Recognition
PubMed: 23796791
DOI: 10.1016/j.dci.2013.06.006 -
Chemical Communications (Cambridge,... Nov 2020The interaction between host immunity and bacterial cells plays a pivotal role in a variety of human diseases. The bacterial cell wall component peptidoglycan (PG) is... (Review)
Review
The interaction between host immunity and bacterial cells plays a pivotal role in a variety of human diseases. The bacterial cell wall component peptidoglycan (PG) is known to stimulate an immune response, which makes PG a distinctive recognition element for unveiling these complicated molecular interactions. Pattern recognition receptor (PRR) proteins are among the critical components of this system that initially recognize molecular patterns associated with microorganisms such as bacteria and fungi. These molecular patterns are mostly embedded in the bacterial or fungal cell wall structure and can be released and presented to the immune system in various situations. Nonetheless, detailed knowledge of this recognition is limited due to the diversity among the PG polymer and its fragments; the subsequent responses by multiple hosts add more complexity. Here, we discuss how our understanding of the role and molecular mechanisms of the well-studied PRR, the NOD-like receptors (NLRs), in the human immune system has evolved in recent years. We highlight the instances of other classes of proteins with similar behavior in the recognition of PG that have been identified in other microorganisms such as yeasts. These proteins are particularly interesting because a network of cellular interactions exists between human host cells, bacteria and yeast as a part of the normal human flora. To support our understanding of these interactions, we provide insight into the chemist's toolbox of peptidoglycan probes that aid in the investigations of the behaviors of these proteins and other biological contexts relevant to the sensing and recognition of peptidoglycan. The importance of these interactions in human health for the development of biomarkers and biotherapy is highlighted.
Topics: Animals; Biosensing Techniques; Host-Pathogen Interactions; Humans; Immunity; Peptidoglycan
PubMed: 33057506
DOI: 10.1039/d0cc02605k -
International Journal of Molecular... Mar 2022The synthesis of a peptidoglycan septum is a fundamental part of bacterial fission and is driven by a multiprotein dynamic complex called the divisome. FtsW and FtsI are... (Review)
Review
The synthesis of a peptidoglycan septum is a fundamental part of bacterial fission and is driven by a multiprotein dynamic complex called the divisome. FtsW and FtsI are essential proteins that synthesize the peptidoglycan septum and are controlled by the regulatory FtsBLQ subcomplex and the activator FtsN. However, their mode of regulation has not yet been uncovered in detail. Understanding this process in detail may enable the development of new compounds to combat the rise in antibiotic resistance. In this review, recent data on the regulation of septal peptidoglycan synthesis is summarized and discussed. Based on structural models and the collected data, multiple putative interactions within FtsWI and with regulators are uncovered. This elaborates on and supports an earlier proposed model that describes active and inactive conformations of the septal peptidoglycan synthesis complex that are stabilized by these interactions. Furthermore, a new model on the spatial organization of the newly synthesized peptidoglycan and the synthesis complex is presented. Overall, the updated model proposes a balance between several allosteric interactions that determine the state of septal peptidoglycan synthesis.
Topics: Bacterial Proteins; Cell Wall; Membrane Proteins; Peptidoglycan
PubMed: 35408901
DOI: 10.3390/ijms23073537 -
Seminars in Cell & Developmental Biology Apr 2019Chemokines are a family of small proteins best known for their ability to orchestrate immune cell trafficking and recruitment to sites of infection. Their role in... (Review)
Review
Chemokines are a family of small proteins best known for their ability to orchestrate immune cell trafficking and recruitment to sites of infection. Their role in promoting host defense is multiplied by a number of additional receptor-dependent biological activities, and most, but not all, chemokines have been found to mediate direct antimicrobial effects against a broad range of microorganisms. The molecular mechanism(s) by which antimicrobial chemokines kill bacteria remains unknown; however, recent observations have expanded our fundamental understanding of chemokine-mediated bactericidal activity to reveal increasingly diverse and complex actions. In the current review, we present and consider mechanistic insights of chemokine-mediated antimicrobial activity against bacteria. We also discuss how contemporary advances are reshaping traditional paradigms and opening up new and innovative avenues of research with translational implications. Towards this end, we highlight a developing framework for leveraging chemokine-mediated bactericidal and immunomodulatory effects to advance pioneering therapeutic approaches for treating bacterial infections, including those caused by multidrug-resistant pathogens.
Topics: Animals; Anti-Infective Agents; Bacteria; Bacterial Infections; Cell Membrane; Cell Wall; Chemokines; Drug Resistance, Bacterial; Humans; Peptidoglycan; Protein Structure, Secondary; Structure-Activity Relationship
PubMed: 29432954
DOI: 10.1016/j.semcdb.2018.02.003