Mode of Action of β-Lactam Antibiotics — A Microbiologist’s View

Tomasz, Alexander

doi:10.1007/978-3-642-81966-7_2

Cited by 6 publications

(6 citation statements)

References 228 publications

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“…However, our conclusion that PBP3 is a killing target is at variance with that of Buchanan & Strominger (1976), who excluded this possibility. In general, inhibition of more than one target PBP is usually required to cause bacterial cell death (Tomasz, 1983). Our results for B. subtilis agree with this general statement since none of the individual PBP mutations was lethal.…”

Section: Discussionsupporting

confidence: 87%

Mutations Affecting Penicillin-binding Proteins 2a, 2b and 3 in Bacillus subtilis Alter Cell Shape and Peptidoglycan Metabolism

Shohayeb¹,

Chopra²

1987

Microbiology

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Bacillus subtilis mutants with altered penicillin-binding proteins (PBPs), or altered expression of PBPs, were isolated by screening for changes in susceptibility to beta-lactam antibiotics. Mutations affecting only PBPs 2a, 2b and 3 were isolated. Cell shape and peptidoglycan metabolism were examined in representative mutants. Cells of a PBP 2a mutant (UB8521) were usually twisted whereas PBP 2b (UB8524) and 3 (UB8525) mutants produced helices, particularly after growth at 41 degrees C. The PBP 2a mutant (UB8521) had a higher peptidoglycan synthetic activity than its parent strain whereas the opposite applied to the PBP 2b mutant UB8524. The PBP 3 mutant (UB8525) had a similar peptidoglycan synthetic activity to that of the parent strain when grown at 37 degrees C, but 40% higher activity after growth at 41 degrees C. The PBP 2a mutant (UB8521) exhibited the same wall thickening activity as the parent, but the PBP 2b and 3 mutants (UB8524 and UB8525) were partially defective in this respect. The changes in the susceptibility of PBP 2a, 2b and 3 mutants to beta-lactam antibiotics imply that these PBPs are killing targets, consistent with the fact that these PBPs are also important for shape determination and peptidoglycan synthesis.

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Section: Discussionsupporting

confidence: 87%

Mutations Affecting Penicillin-binding Proteins 2a, 2b and 3 in Bacillus subtilis Alter Cell Shape and Peptidoglycan Metabolism

Shohayeb¹,

Chopra²

1987

Microbiology

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“…This is also supported by analysis of structural relatedness, since among the E. coli PBPs, chlamydial PBP1 has highest homology to E. coli PBP2 (7). Although PBP2 is required for the maintenance of cell shape in E. coli (4,5,23), the lethality of PBP2 inactivation has also been attributed to cell division inhibition (26). If chlamydial PBP1, by analogy, is involved in cell division, this would be consistent with our hypothesis (3) that in chlamydia PG, or a glycanless PG-like polymer, has a major role in RB division.…”

supporting

confidence: 86%

“…In other bacteria PBPs have roles in peptidoglycan (PG) metabolism through their activities as transpeptidases, carboxypeptidases, and endopeptidases (6,23). Chlamydiae possess three PBPs, and although genomic analysis assigns transpeptidase activity to PBP1 and PBP2 (3,7) and carboxypeptidase activity to PBP3 (3, 7), a major paradox of chlamydial biology is the inability to detect PG, or a PG-like polymer, in these organisms (1,3,7,16).…”

mentioning

confidence: 99%

Affinities of β-Lactams for Penicillin Binding Proteins of Chlamydia trachomatis and Their Antichlamydial Activities

Storey

Chopra

2001

Antimicrob Agents Chemother

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Binding affinities of ␤-lactam antibiotics for the three penicillin binding proteins (PBPs) from Chlamydia trachomatis were determined in vitro and compared with their antichlamydial activities. Mecillinam selectively inhibited PBP1, with a 50% inhibitory concentration for PBP1 binding (0.2 g/ml) similar to the MIC (0.1 g/ml) and minimum bactericidal concentration (0.25 g/ml). Although the other ␤-lactams inhibited a wider range of PBPs than mecillinam, their antichlamydial activities were inferior to that of mecillinam.

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“…Bar,5 ,um. bacter cloacae, in which high affinities for both PBP 2 and PBP 3 were also reported for cefepime (23). Few other cephalosporins show this combination of high affinity for PBP 2 and 3 in the Enterobacteriaceae family (23,24). No correlation between MICs and PBP affinities was evident for P. aeruginosa SC8329.…”

Section: Discussionmentioning

confidence: 99%

Comparison of cefepime, cefpirome, and cefaclidine binding affinities for penicillin-binding proteins in Escherichia coli K-12 and Pseudomonas aeruginosa SC8329

Pucci

Boice-Sowek

Kessler

et al. 1991

Antimicrob Agents Chemother

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The relative binding affinities of the extended-spectrum cephalosporins cefepime, cefpirome, and cefaclidine for the penicillin-binding proteins (PBPs) of Escherichia coli K-12 and Pseudomonas aeruginosa SC8329 were determined. Affinities were calculated from competition experiments between these antibiotics and [3H]benzylpenicillin in isolated membrane preparations. The concentrations which reduced binding to a PBP by 50% (IC50s) were determined. For E. coli, all three antibiotics displayed good PBP 3 binding (IC50s of 0.5 ,ug/ml or less), and MICs roughly correlated with these values. Cefepime had a greater than 20-fold-lower IC50 for PBP 2 of E. coli than the other antibiotics. For P. aeruginosa, all of the antibiotics bound poorly (>25 ,ug/ml) to PBP 2 but showed excellent pseudomonal (<0.0025 ,ig/ml) PBP 3 binding. No correlations were seen between IC50sand MICs for P. aeruginosa. Despite differences in PBP binding, cefepime, cefpirome, and cefaclidine all displayed similar bactericidal activity for E. coli K-12 over the initial 3 h after antibiotic addition. All three caused E. coli to form filaments at values close to the MICs. In addition, cefepime induced "bleb" formation along the filaments at concentrations >10x the MIC.

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Mode of Action of β-Lactam Antibiotics — A Microbiologist’s View

Cited by 6 publications

References 228 publications

Mutations Affecting Penicillin-binding Proteins 2a, 2b and 3 in Bacillus subtilis Alter Cell Shape and Peptidoglycan Metabolism

Mutations Affecting Penicillin-binding Proteins 2a, 2b and 3 in Bacillus subtilis Alter Cell Shape and Peptidoglycan Metabolism

Affinities of β-Lactams for Penicillin Binding Proteins of Chlamydia trachomatis and Their Antichlamydial Activities

Comparison of cefepime, cefpirome, and cefaclidine binding affinities for penicillin-binding proteins in Escherichia coli K-12 and Pseudomonas aeruginosa SC8329

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