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Constructing and deconstructing the bacterial cell wall.

ABSTRACT: The history of modern medicine cannot be written apart from the history of the antibiotics. Antibiotics are cytotoxic secondary metabolites that are isolated from Nature. The antibacterial antibiotics disproportionately target bacterial protein structure that is distinct from eukaryotic protein structure, notably within the ribosome and within the pathways for bacterial cell-wall biosynthesis (for which there is not a eukaryotic counterpart). This review focuses on a pre-eminent class of antibiotics-the ?-lactams, exemplified by the penicillins and cephalosporins-from the perspective of the evolving mechanisms for bacterial resistance. The mechanism of action of the ?-lactams is bacterial cell-wall destruction. In the monoderm (single membrane, Gram-positive staining) pathogen Staphylococcus aureus the dominant resistance mechanism is expression of a ?-lactam-unreactive transpeptidase enzyme that functions in cell-wall construction. In the diderm (dual membrane, Gram-negative staining) pathogen Pseudomonas aeruginosa a dominant resistance mechanism (among several) is expression of a hydrolytic enzyme that destroys the critical ?-lactam ring of the antibiotic. The key sensing mechanism used by P. aeruginosa is monitoring the molecular difference between cell-wall construction and cell-wall deconstruction. In both bacteria, the resistance pathways are manifested only when the bacteria detect the presence of ?-lactams. This review summarizes how the ?-lactams are sensed and how the resistance mechanisms are manifested, with the expectation that preventing these processes will be critical to future chemotherapeutic control of multidrug resistant bacteria.

SUBMITTER: Fisher JF

PROVIDER: S-EPMC7021008 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Constructing and deconstructing the bacterial cell wall.

Fisher Jed F JF Mobashery Shahriar S

Protein science : a publication of the Protein Society 20191120 3

The history of modern medicine cannot be written apart from the history of the antibiotics. Antibiotics are cytotoxic secondary metabolites that are isolated from Nature. The antibacterial antibiotics disproportionately target bacterial protein structure that is distinct from eukaryotic protein structure, notably within the ribosome and within the pathways for bacterial cell-wall biosynthesis (for which there is not a eukaryotic counterpart). This review focuses on a pre-eminent class of antibio ...[more]

PMID: 31747090

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Project description: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.IMPORTANCE 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.

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Constructing and deconstructing the bacterial cell wall.

Publications

Constructing and deconstructing the bacterial cell wall.

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