Beta-lactamase stability and antibacterial activity of cefmenoxime (SCE-1365), a novel cephalosporin

Okonogi, Kenji; Kuno, Mitsuzo; Kida, Makoto; Mitsuhashi, Susumu

doi:10.1128/aac.20.2.171

Cited by 33 publications

(14 citation statements)

References 21 publications

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“…vulgaris (10). In our study, these aminothiazolyl-oxyimino cephalosporins, except for ceftizoxime and ceftazidime, showed significantly high Vmax values.…”

Section: Discussionmentioning

confidence: 75%

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Paradoxical antibacterial activities of beta-lactams against Proteus vulgaris: mechanism of the paradoxical effect

Ikeda

Nishino

1988

Antimicrob Agents Chemother

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Fifteen I8-lactam antibiotics were divided into four classes based on their antibacterial actions and ,l-lactamase-inducing activities in Proteus vulgaris. One of these groups, which included cefmenoxime, ceftriaxone, cefuzonam, and cefotaxime, showed a clear paradoxical antibacterial activity against P. vulgaris. This group showed growth-inhibitory activity at relatively low concentrations, up to certain limits. These cephalosporins have, as a common moiety, an aminothiazolyl-oxyimino group in the 7-acyl side chain and have high P-lactamase-inducing activities and low stabilities against the f-lactamase. In a mutant strain incapable of inducing P-lactamase, however, the paradoxical antibacterial activity was not observed. These findings suggest that ,3-lactamase plays an essential role in the paradoxical antibacterial effect in P. vulgaris. We conclude that the induction of a large amount of P-lactamase and the low stability against ,3-lactamase may account for the paradoxical antibacterial activity in P. vulgaris.It is generally assumed that antibacterial activity is proportional to the drug concentration. However, several exceptional observations have been reported (1, 2, 7). Eagle and Musselman (2) have observed that the activity of penicillin G against gram-positive cocci falls off as its concentration is increased. Similar paradoxical effects of antibiotics have been reported (1, 7). In these reports, the mechanisms of the paradoxical phenomena have not been explained.In our previous paper (4), we reported that cefmenoxime showed paradoxical antibacterial activity against several strains of Proteus vulgaris and that this paradoxical effect was dependent on the P-lactamase inductivity and the stability against the ,-lactamase that was induced.Cefmenoxime is one of the new type of cephalosporins and is modified in its 7-acyl side chain with an aminothiazolyl group (10). The cephalosporins with aminothiazolyl groups are not as stable against the ,-lactamase specific to P. vulgaris (13). Thus, if the paradoxical effect is actually dependent only on the enzymatic characteristics (of the 1-lactam antibiotic), the paradoxical theory should be applicable to other aminothiazolyl cephalosporins.In this study, we explored this paradoxical mechanism in P. vulgaris by using 15 ,-lactam antibiotics and confirmed a causal relationship between the paradoxical antibacterial effect and the enzymatic characteristics of the 3-lactam antibiotic. MATERIALS AND METHODSBacterial strains. P. vulgaris 11, a strain that has been described previously (4), and P. vulgaris 11-S, a P-lactamase-noninducing mutant of P. vulgaris 11, were used in this study. P. vulgaris 11-S was derived by mutagenesis with selection, based on its susceptibility to cephaloridine and ampicillin.A logarithmic-phase culture of P. vulgaris 11 was treated with 25 ,ug of N-methyl-N'-nitro-N-nitrosoguanidine per ml for 20 min at 37°C. The washed and treated cells were inoculated in sensitivity broth (Eiken Chemical, Tokyo,

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“…vulgaris (10). In our study, these aminothiazolyl-oxyimino cephalosporins, except for ceftizoxime and ceftazidime, showed significantly high Vmax values.…”

Section: Discussionmentioning

confidence: 75%

“…Cefmenoxime is one of the new type of cephalosporins and is modified in its 7-acyl side chain with an aminothiazolyl group (10). The cephalosporins with aminothiazolyl groups are not as stable against the ,-lactamase specific to P. vulgaris (13).…”

mentioning

confidence: 99%

Paradoxical antibacterial activities of beta-lactams against Proteus vulgaris: mechanism of the paradoxical effect

Ikeda

Nishino

1988

Antimicrob Agents Chemother

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“…P-Lactamase activity was determined by a direct spectrophotometric method as described previously (7) or by a modification of the microiodometric method (15 Other methods. Determination of protein (11), isoelectric focusing, ultrafiltration, determination of molecular weight (2,10), and inhibition studies were carried out according to the procedures described previously (17).…”

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confidence: 99%

Purification and properties of an inducible cephalosporinase from Pseudomonas maltophilia GN12873

Saino¹,

Inoue²,

Mitsuhashi³

1984

Antimicrob Agents Chemother

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An inducible cephalosporinase was purified from Pseudomonas maltophilia GN12873. The pI was 8.4, and the molecular weight was ca. 56,000 by gel filtration or 27,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, suggesting that this enzyme had two subunits. The optimal pH and optimal temperature were 7.5 and 45°C, respectively. Enzyme activity was inhibited by clavulanic acid, sulbactam, cephamycin derivatives, carbapenem antibiotics, iodine, HgCI2, and p-chloromercuribenzoate. The enzyme showed a broad substrate profile, hydrolyzing cephaloridine, cefazolin, cefsulodin, penicillin G, ceftizoxime, and ampicillin at a high rate.There have not been many investigations of the P-lactamases of Pseudomonas maltophilia, even though most clinical isolates of this organism are resistant to many P-lactam antibiotics, including imipenem (N-formimidoyl thienamycin) and aztreonam (6,8,9,14).Recently we reported that seven strains of P. maltophilia produced two types of ,B-lactamase, designated as L-1 and L-2 (17, 18). The L-1 enzyme purified from the representative strain GN12873 was found to be a new type of penicillinase from its unusual enzymological properties. The L-2 enzyme appeared to be a cephalosporinase and seemed to play an important role in the resistance mechanisms of P. maltophilia to various cephalosporins.The present paper compares the physicochemical and enzymological properties of the L-2 enzyme produced by P. maltophilia GN12873 with other P-lactamases.MATERIALS AND METHODS Bacterial strain. Strain GN12873 is a clinical isolate of P. maltophilia. It was stored at -80°C in skim milk containing 5% glucose (pH 7.4).

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“…After the assay was allowed to stand for 15 min, the A260 of the assay and that of a blank were read. The enzyme activity was calculated from the difference between the assay and the blank; one absorbance unit was equivalent to 30 nmol of penicillin G hydrolyzed (15 DSM 158 25 3 6 6 6 13 50 13 25 13 13 1 DSM 159 25 3 1 3 2 3 200 50 50 13 13 1 DSM 160 50 6 6 6 3 13 400 400 200 25 25 1 Y-1 50 3 2 2 2 6 200 200 200 25 50 1 Neal 25 3 2 3 2 6 400 400 100 25 25 1 Nea2 50 2 2 6 3 13 100 50 50 25 CeUlular location of P-lagtamase. Table 3 shows the distribution of the P-lactamase activity in various fractions of a culture grown in the presence of penicillin G (50 ,ug ml-) in LB medium.…”

Section: Methodsmentioning

confidence: 99%

Susceptibility of Rhodobacter sphaeroides to beta-lactam antibiotics: isolation and characterization of a periplasmic beta-lactamase (cephalosporinase)

et al. 1989

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Thirteen strains of the gram-negative, facultative phototrophic bacterium Rhodobacter sphaeroides were examined for susceptibility to ,-lactam antibiotics. All strains were sensitive to the semisynthetic penicillins ampiciflin, carbenicillin, oxacillin, cloxacillin, and methicillin, but 10 of the 13 strains were resistant to penicillin G, as well as a number of cephalosporins, such as cephalothin, cephapirin, and cephalosporin C. A ,1-lactamase (EC 3.5.2.6) with strong cephalosporinase activity was detected in all of the resistant strains of R. sphaeroides. With strain Y-1 as a model, it was shown that the (-lactamase was inducible by penicillin G, cephalosporin C, cephalothin, and to some minor extent, cephapirin. The j-lactamase was located in the periplasmic space, from which it could be extracted by osmotic shock disruption. By using this fraction, the j-lactamase was purified 34-fold to homogeneity by steps involving batch adsorption to and elution from DEAE-Sephadex A50, chromatography on Q-Sepharose, and preparative polyacrylamide gel electrophoresis. The molecular masses of the native and denatured enzymes were determined to be 38.5 kilodaltons by gel filtration and 40.5 kilodaltons by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, respectively, indicating a monomeric structure. The isoelectric point was estimated to be at pH 4.3. In Tris hydrochloride buffer, optimum enzyme activity was measured at pH 8.A. The j8-lactamase showed high activity in the presence of the substrates cephalothin, cephapirin, cephalosporin C, and penicillin G, for which the apparent Km values were 144, 100, 65, and 110 ,iM, respectively. Cephalexin, cepharidine, and cephaloridine were poor substrates. The j-lactamase was strongly inhibited by cloxacillin and oxacillin but only slightly inhibited by phenylmethylsulfonyl fluoride or thiol reagents such as iodoacetate and p-chloromercuribenzoate.Bacterial resistance to penicillins or cephalosporins is associated primarily with the formation of 13-lactamases (EC 3.5.2.6) (18). Although strains of the facultative phototrophic bacterium Rhodobacter sphaeroides have been reported to be remarkably resistant to penicillin, as well as a number of semisynthetic penicillins (14,16,17), the enzymes that mediate such resistances in photosynthetic bacteria have not been studied. Only penicillin-binding proteins of R. sphaeroides 2.4.1 have been characterized in terms of size and cellular localization (22).In the present communication, we show that most of our R. sphaeroides wild-type iso-lates were resistant to penicillin and a number of cephalosporins but not to semisynthetic penicillins. Resistance was associated with a periplasmic P-lactamase whose isolation from a phototrophic bacterium and characterization are reported for the first time. MATERIALS AND METHODSBacterial strains. R. sphaeroides is a purple nonsulfur bacterium. Strains DSM 158 (identical to ATCC 17023, NCIB 8253, and ATH 2.4.1), DSM 159 (1760-1), and DSM 160 (Y) were obtained from the German Collection of Microo...

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Beta-lactamase stability and antibacterial activity of cefmenoxime (SCE-1365), a novel cephalosporin

Cited by 33 publications

References 21 publications

Paradoxical antibacterial activities of beta-lactams against Proteus vulgaris: mechanism of the paradoxical effect

Paradoxical antibacterial activities of beta-lactams against Proteus vulgaris: mechanism of the paradoxical effect

Purification and properties of an inducible cephalosporinase from Pseudomonas maltophilia GN12873

Susceptibility of Rhodobacter sphaeroides to beta-lactam antibiotics: isolation and characterization of a periplasmic beta-lactamase (cephalosporinase)

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