New Antipseudomonal Penicillin, PC-904: Affinity to Penicillin-Binding Proteins and Inhibition of the Enzyme Cross-Linking Peptidoglycan

Noguchi, Hiroshi; Matsuhashi, Michio; Takaoka, Masayoshi; Mitsuhashi, Susumu

doi:10.1128/aac.14.4.617

Cited by 27 publications

(21 citation statements)

References 16 publications

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“…Preliminary results of research on the affinity of cefotaxime for the penicillin-binding proteins (PBPs) of P. aeruginosa (7), done by S. it is imperative, we think, that experiments similar to ours be done with many more analogs and other derivatives of cefotaxime. Conclusions from these will allow for our better understanding of the structure-versus-activity relationship that has eluded us until now.…”

Section: Discussionmentioning

confidence: 87%

Biosynthesis of peptidoglycan in Pseudomonas aeruginosa: comparison of the inhibitory effects of cefotaxime, its anti isomer, and the syn S-oxide compound

Mirelman¹,

Nuchamowitz²

1980

Antimicrob Agents Chemother

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The intrinsic effect of three novel methoxyimino derivatives of cephalosporin (cefotaxime [syn HR 756]; its anti isomer, R 02 5328 A; and the syn S-oxide derivative, HR 109) on the biosynthesis of peptidoglycan ofPseudomonas aeruginosa X-48 was investigated. Cefotaxime at very low concentrations (50% inhibition at 0.025 ,ug/ml) inhibited the transpeptidase reaction which catalyzes the incorporation and attachment of newly synthesized peptidoglycan to the preexisting cell wall sacculus. The S-oxide compound, HR 109, was a much less efficient inhibitor of this reaction (50% inhibition at 0.55 ,ug/ml), whereas the anti isomer of cefotaxime, R 02 5328 A, had no inhibitory effect. All three compounds were quite similar in being relatively poor inhibitors of D-alanine carboxypeptidase.As previously described (3,4), the biosynthesis of peptidoglycan of Pseudomonas aeruginosa and the enzyme complex which cross-links the peptidoglycan appear to be somewhat similar to those found in Escherichia coli. They consist mainly of a transpeptidase and a DD-carboxypeptidase-endopeptidase system (1, 3, 5). A considerable number of f?-lactam antibiotics have been shown to inhibit these reactions to various degrees. In the present communication, we describe the effects of three novel compounds which are oxime derivatives of cephalosporins. One of these compounds, cefotaxime (HR 756), has been found to have excellent in vivo activity (2, 6) against a wide variety ofbacteria, including P. aeruginosa, and was therefore studied in greater detail. To try to better understand any possible relationship between the structure and the activity of this promising compound, we carried out a comparison of its intrinsic activity at the enzymatic level with two compounds which have closely related structures (Fig. 1), the anti isomer, R 02 5328 A, and the syn Soxide derivative, HR 109. cpmn'/pmol1'), with or without the addition of UDPMurNAc-pentapeptide (50 nmol), as previously described (3, 5). Incubations were for 60 min at 37°C, and determination of peptidoglycan insoluble in trichloroacetic acid and sodium dodecyl sulfate, as well as peptide cross-linkage formations, were as described (3). Determinations of DD-carboxypeptidase and transpeptidase activity were done in assays containing UDP-MurNAc-L-Ala-D-Glu-ms-A2pm-D-Ala-D-["C]-Ala (100,000 cpm, 15 cpm-1/pmol['), with or without UDP-GlcNAc (50 nmol), as described (3, 5). MATERIALS AND METHODSGrowth inhibition. A known amount of antibiotic solutions was placed in a filter paper disk and allowed to dry. The disk was added to a plate (antibiotic no. 3 medium; Difco Laboratories), inoculated with P.aeruginosa X-48, and incubated overnight at 370C.

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Section: Discussionmentioning

confidence: 87%

Biosynthesis of peptidoglycan in Pseudomonas aeruginosa: comparison of the inhibitory effects of cefotaxime, its anti isomer, and the syn S-oxide compound

Mirelman¹,

Nuchamowitz²

1980

Antimicrob Agents Chemother

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“…Noguchi and colleagues have clearly shown that the increased activity of apalcillin is due to its high affinity for penicillin-binding proteins (9,10). The discrepancy between MIC and MBC values and the inoculum effect are clearly due to the P-lactamase instability of apalcillin.…”

Section: Resultsmentioning

confidence: 99%

In vitro activity of apalcillin compared with that of other new penicillins and anti-Pseudomonas cephalosporins

Neu¹,

Labthavikul²

1982

Antimicrob Agents Chemother

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Apalcillin, a naphthydridine derivative of ampicillin, was compared with ticarcillin, azlocillin, mezlocillin, piperacillin, cefotaxime, and cefoperazone against gram-negative and gram-positive bacterial isolates and with cefsulodin and tobramycin against Pseudomonas aeruginosa. The minimal concentrations of apalcillin at which 50 and 90% of hospital isolates of Escherichia coli were inhibited were similar to those of mezlocillin and piperacillin (1.6 and 100 ,ug/ml, respectively). Apalcillin had minimal inhibitory concentrations similar to those of piperacillin against Citrobacterfreundii and Citrobacter diversus. Against Klebsi-ella, apalcillin inhibited 50% of organisms at a concentration of 6.3 ,ug/ml, similar to piperacillin. The activity of apalcillin against Enterobacter (E. aerogenes, E. cloacae, and E. agglomerans) was similar to that of mezlocillin and piperacillin and greater than that of ticarcillin. The activity of apalcillin against Proteus mirabilis was similar to that of the other agents, as was its activity against indolepositive Proteus and Providencia. Only 40% of Serratia were inhibited at an apalcillin concentration of 25 ,ug/ml. Apalcillin was as active as piperacillin but twofold less active than cefoxitin or moxalactam against Bacteroides fragilis. It was as active as piperacillin, cefoperazone, and cefsulodin against P. aeruginosa (apalcillin inhibited 90% of organisms at a concentration of 25 mg/ml). There was an inoculum effect and a difference in the minimal inhibitory concentration and minimal bactericidal concentration with 3-lactamase strains. Apalcillin was hydrolyzed by plasmid P-lactamase but not as well by cephalosporinases.

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“…In β-lactam-treated cells of E. coli and P. aeruginosa, this change has been attributed to inhibition of PBP3 [75,119]. PBP3 crosslinks peptidoglycan at the septal wall but not the lateral wall, so inhibition of this enzyme results in cell elongation without division [58,86].…”

Section: Filamentationmentioning

confidence: 99%

Morphological and ultrastructural changes in bacterial cells as an indicator of antibacterial mechanism of action

Cushnie

O’Driscoll

Lamb

2016

Cell. Mol. Life Sci.

159

124

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New Antipseudomonal Penicillin, PC-904: Affinity to Penicillin-Binding Proteins and Inhibition of the Enzyme Cross-Linking Peptidoglycan

Cited by 27 publications

References 16 publications

Biosynthesis of peptidoglycan in Pseudomonas aeruginosa: comparison of the inhibitory effects of cefotaxime, its anti isomer, and the syn S-oxide compound

Biosynthesis of peptidoglycan in Pseudomonas aeruginosa: comparison of the inhibitory effects of cefotaxime, its anti isomer, and the syn S-oxide compound

In vitro activity of apalcillin compared with that of other new penicillins and anti-Pseudomonas cephalosporins

Morphological and ultrastructural changes in bacterial cells as an indicator of antibacterial mechanism of action

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