Breaking down the cell wall: Strategies for antibiotic discovery targeting bacterial transpeptidases

Cochrane, Stephen A.; Lohans, Christopher T.

doi:10.1016/j.ejmech.2020.112262

Cited by 41 publications

(28 citation statements)

References 103 publications

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“…In contrast, acylation of the serine nucleophile at the transpeptidase/carboxypeptidase active sites of the PBPs by βlactam antibiotics is irreversible. 190,191 Thus, upon exposure of PBPs to high concentration of radioactive β-lactams (as the relative affinity of a given β-lactam for a given PBP is variable), all of the PBPs of a bacterium are inactivated by this acylation. 192,193 These radiochemically labeled PBPs are sorted by molecular mass using electrophoresis.…”

Section: Cell Envelope Of the Gram-positive Bacteriummentioning

confidence: 99%

“…The latter substrates are competent for acyl-transfer, by initial transfer of the penultimate d -Ala to an active-site serine to form an acyl-enzyme, that is then transferred in the second half-reaction to the fifth glycine (in S. aureus ) to effect cross-linking. In contrast, acylation of the serine nucleophile at the transpeptidase/carboxypeptidase active sites of the PBPs by β-lactam antibiotics is irreversible. , Thus, upon exposure of PBPs to high concentration of radioactive β-lactams (as the relative affinity of a given β-lactam for a given PBP is variable), all of the PBPs of a bacterium are inactivated by this acylation. , These radiochemically labeled PBPs are sorted by molecular mass using electrophoresis. This analysis is done today using labeling with fluorescent β-lactams. − The highest molecular mass PBP of the bacterium is designated as its PBP1.…”

Section: Gram-positive Cell Envelopementioning

confidence: 99%

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β-Lactams against the Fortress of the Gram-Positive Staphylococcus aureus Bacterium

Fisher

Mobashery

2020

Chem. Rev.

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The biological diversity of the unicellular bacteriawhether assessed by shape, food, metabolism, or ecological nichesurely rivals (if not exceeds) that of the multicellular eukaryotes. The relationship between bacteria whose ecological niche is the eukaryote, and the eukaryote, is often symbiosis or stasis. Some bacteria, however, seek advantage in this relationship. One of the most successfulto the disadvantage of the eukaryoteis the small (less than 1 μm diameter) and nearly spherical Staphylococcus aureus bacterium. For decades, successful clinical control of its infection has been accomplished using β-lactam antibiotics such as the penicillins and the cephalosporins. Over these same decades S. aureus has perfected resistance mechanisms against these antibiotics, which are then countered by new generations of β-lactam structure. This review addresses the current breadth of biochemical and microbiological efforts to preserve the future of the β-lactam antibiotics through a better understanding of how S. aureus protects the enzyme targets of the β-lactams, the penicillin-binding proteins. The penicillin-binding proteins are essential enzyme catalysts for the biosynthesis of the cell wall, and understanding how this cell wall is integrated into the protective cell envelope of the bacterium may identify new antibacterials and new adjuvants that preserve the efficacy of the β-lactams.

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Section: Cell Envelope Of the Gram-positive Bacteriummentioning

confidence: 99%

Section: Gram-positive Cell Envelopementioning

confidence: 99%

β-Lactams against the Fortress of the Gram-Positive Staphylococcus aureus Bacterium

Fisher

Mobashery

2020

Chem. Rev.

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“…PG surrounds the whole cell, provides major mechanical support against turgor pressure, and defines cell shape throughout the life cycles of most bacteria [ 25 ]. As PG is chemically unique, and usually essential for cell survival, the synthesis and turnover of PG have been predominant targets for antibacterial treatments [ 26 ].…”

Section: Pg and Cell Shapementioning

confidence: 99%

Myxococcus xanthus as a Model Organism for Peptidoglycan Assembly and Bacterial Morphogenesis

2021

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A fundamental question in biology is how cell shapes are genetically encoded and enzymatically generated. Prevalent shapes among walled bacteria include spheres and rods. These shapes are chiefly determined by the peptidoglycan (PG) cell wall. Bacterial division results in two daughter cells, whose shapes are predetermined by the mother. This makes it difficult to explore the origin of cell shapes in healthy bacteria. In this review, we argue that the Gram-negative bacterium Myxococcus xanthus is an ideal model for understanding PG assembly and bacterial morphogenesis, because it forms rods and spheres at different life stages. Rod-shaped vegetative cells of M. xanthus can thoroughly degrade their PG and form spherical spores. As these spores germinate, cells rebuild their PG and reestablish rod shape without preexisting templates. Such a unique sphere-to-rod transition provides a rare opportunity to visualize de novo PG assembly and rod-like morphogenesis in a well-established model organism.

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“…In vitro, this technique can switch the terminal D-Ala for biotinylated D-Lys (BDL); biotinylated Lipid II is then detectable via western blot (Figure 2B). This technique provides Review researchers with a streamlined process to obtain functionalized Lipid II analogs that can be selectively detected, thus generating a valuable assay for studying PG biosynthetic machinery and screening antibiotics (Cochrane and Lohans, 2020).…”

Section: Using Antibiotics To Isolate Cell Wall Intermediatesmentioning

confidence: 99%

Chemical Biology Tools for Examining the Bacterial Cell Wall

Brown

Gordon

Hyland

et al. 2020

Cell Chemical Biology

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Bacteria surround themselves with cell walls to maintain cell rigidity and protect against environmental insults. Here we review chemical and biochemical techniques employed to study bacterial cell wall biogenesis. Recent advances including the ability to isolate critical intermediates, metabolic approaches for probe incorporation, and isotopic labeling techniques have provided critical insight into the biochemistry of cell walls. Fundamental manuscripts that have used these techniques to discover cell wall-interacting proteins, flippases, and cell wall stoichiometry are discussed in detail. The review highlights that these powerful methods and techniques have exciting potential to identify and characterize new targets for antibiotic development. ll ll

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Breaking down the cell wall: Strategies for antibiotic discovery targeting bacterial transpeptidases

Abstract: Accepted/In press). Breaking down the cell wall: strategies for antibiotic discovery targeting bacterial transpeptidases. European journal of medicinal chemistry.

Cited by 41 publications

References 103 publications

β-Lactams against the Fortress of the Gram-Positive Staphylococcus aureus Bacterium

β-Lactams against the Fortress of the Gram-Positive Staphylococcus aureus Bacterium

Myxococcus xanthus as a Model Organism for Peptidoglycan Assembly and Bacterial Morphogenesis

Chemical Biology Tools for Examining the Bacterial Cell Wall

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