Comparative Stability of Newly Introduced β-Lactam Antibiotics to Renal Dipeptidase

Mikami, Hidetada; Ogashiwa, Motohide; Saino, Yushi; Inoue, Matsuhisa; Mitsuhashi, Susumu

doi:10.1128/aac.22.4.693

Cited by 19 publications

(9 citation statements)

References 14 publications

(9 reference statements)

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“…Hydrolysis was assayed spectrophotometrically as described previously (2,8,13). One unit of the enzyme was defined as the amount of the enzyme which hydrolyzed 1 ,umol of a substrate per min at 35°C.…”

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confidence: 99%

“…The kinetic parameters of the enzyme are shown in Purification of human dehydropeptidase by a previously described treatment (8) was unsuccessful, since enzyme activity was lost. Shibamoto et al (9) reported that PS-5 inactivating factor was fractionated by the differential cen-ANTIMICROB.…”

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confidence: 99%

“…We have previously reported on the comparative stability of newly introduced P-lactam antibiotics against purified swine renal dipeptidase (8). Knowledge of in vivo metabolism and of in vitro hydrolysis by renal dehydropeptidase of carbapenem antibiotics is essential for the practical chemical evaluation of carbapenem derivatives.…”

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confidence: 99%

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Purification and characterization of human renal dehydropeptidase I

Mitsuhashi¹,

Fuse²,

Mikami³

et al. 1988

Antimicrob Agents Chemother

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confidence: 99%

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confidence: 99%

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Purification and characterization of human renal dehydropeptidase I

Mitsuhashi¹,

Fuse²,

Mikami³

et al. 1988

Antimicrob Agents Chemother

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“…Renal dehydropeptidase 1 was purified from hog kidney cortex by the procedure described previously (8 …”

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“…Renal dehydropeptidase 1 was purified from hog kidney cortex by the procedure described previously (8). Hydrolysis of the compounds was assayed spectrophotometrically (1) by measuring the decrease in absorbance at the substrate-specific wavelength in a temperature-controlled spectrophotometer (8).…”

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In vitro antibacterial activity of Sch 34343 and its stability to beta-lactamases and renal dehydropeptidase 1

Matsuda¹,

Sasaki²,

Inoue³

et al. 1985

Antimicrob Agents Chemother

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The in vitro antibacterial activity of Sch 34343 against 1,328 strains of clinical isolates was compared with those of imipenem and ceftazidime. Sch 34343 had a broad spectrum of antibacterial activity against both gram-positive and gram-negative bacteria but was inactive against Pseudomonas aeruginosa and Pseudomonas maltophilia. Sch 34343 was quite stable to hydrolysis by j-lactamases, including both penicillinases and cephalosporinases. However, Sch 34343 was slightly hydrolyzed by a new type of I8-lactamase (oxyiminocephalosporin ,I-lactamase), as was imipenem. Sch 34343 was slightly hydrolyzed by renal dehydropeptidase 1 but was somewhat more stable than other carbapenems.Many kinds of P-lactam antibiotics have been used clinically for the treatment of a wide range of bacterial infections. Recently, however, the effectiveness of the existing ,B-lactam antibiotics has been shown to be limited by a speedy increase in clinical infections caused by bacteria resistant to ,-lactam antibiotics (13). Much effort has been expended in developing broad-spectrum antibiotics with resistance to ,-lactamases. Recently, nontraditional 1-lactam antibiotics such as carbapenems (5) Determination of MICs. MICs were determined by a twofold serial agar dilution method. For Bacteroides fragilis and streptococci, Gifu anaerobic medium agar and sensitivity disk agar supplemented with 5% defibrinated horse blood were used, respectively. For Haemophilus influenzae, sensitivity disk agar containing 10 ,ug of hemin and 5 ,ug of P-NAD per ml was used. All antibiotic solutions were freshly made on the day of use. The test organism was grown overnight at 37°C in sensitivity test broth for preculture, unless otherwise specified. The other media used were as follows: sensitivity test broth containing 0.4% potassium nitrate for Pseudomonas aeruginosa, brain heart infusion agar for streptococci, sensitivity test broth supplemented with 10 ,Lg of hemin and 2 ,g of ,B-NAD per ml for H. influenzae, and Gifu anaerobic medium broth for B. fragilis. Overnight cultures of tested strains were diluted, and about 3 x 104 CFU was applied to the agar surface with an inoculator (Microplanter; Sakuma Seisakusho, Tokyo). Plates were incubated for 18 h at 37°C. B. fragilis was incubated for 24 h at 37°C under anaerobic conditions. The MIC was defined as the lowest concentration of the antibiotic that prevented visible growth.Stability to ,I-lactamase. Various types of ,B-lactamase (10) used in this study were purified by the methods described previously (2,4,6,7,9,14,(16)(17)(18)20). P-Lactamase activity was determined by the spectrophotometric method (21). For determining the rate of hydrolysis, the molecular absorbancy difference (A/E) and the specific wavelength for Sch 34343 were 67,450 M-1 cm-1 and 330 nm, respectively. For other substrates, A1E and the specific wavelength were described previously (11). Enzymatic reaction was carried out at 30°C in a waterjacketed spectrophotometer (model 24; Beckman Instruments, Inc., Fullerton, Calif.).The Michaelis ...

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β‐Lactamase Inhibitors

Stam

2000

Kirk-Othmer Encyclopedia of Chemical Technology

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The antibacterial effectiveness of penicillins, cephalosporins, and other β‐lactam antibiotics depends on the inactivation of transpeptidases involved in bacterial cell wall synthesis. Bacteria that are resistant to β‐lactam antibiotics often produce enzymes called β‐lactamases that inactivate the antibiotics by catalyzing the hydrolytic opening of the β‐lactam ring to give products devoid of antibacterial activity. One approach to combating antibiotic resistance caused by β‐lactamase is to inhibit the enzyme. Effective combinations of enzyme inhibitors with β‐lactam antibiotics such as penicillins or cephalosporins result in a synergistic response, lowering the minimal inhibitory concentration (MIC) by a factor of four or more for each component. However, pharmacokinetics, stability, ability to penetrate bacteria, cost, and other factors are also important in determining whether an inhibitor is suitable for therapeutic use. The most important β‐lactamases to inhibit clinically are the gram‐positive penases, the gram‐negative TEM, which are Richmond‐Sykes type III, and the gram‐negative chromosomal cephalosporinases–cephases which are Richmond‐Sykes type I. These enzymes may be referred to as penase, TEM(III), and cephase(I). These clinically important β‐lactamases are serine proteases that form an acyl enzyme intermediate with β‐lactam substrates and β‐lactam‐derived β‐lactamase inhibitors. A number of β‐lactamase‐resistant penicillins and cephalosporins were found to be β‐lactamase inhibitors. No clinically useful inhibitors have been identified from this class. Clavulanic acid has only weak antibacterial activity, but is a potent irreversible inhibitor for many clinically important β‐lactamases, including penases and Richmond‐Sykes types II, III, IV, V, VI ( Bacteroides ). Carbapenems are another class of natural product β‐lactamase inhibitors. Many penem β‐lactamase inhibitors are potent antibacterials. Penicillanic acid sulfone, (2( S )‐ cis )‐3,3‐dimethyl‐7‐oxo‐4,4‐dioxide‐4‐thia‐1‐azabicyclo [3.2.0]heptane‐2‐carboxylic acid (sulbactam) ( , ), C 8 H 11 NO 5 S, is a weak antibacterial, but is a potent irreversible inactivator of many β‐lactamases, including penases and Richmond‐Sykes type II, III, IV, V, and VI ( Bacteroides ) β‐lactamases. Sulbactam is better than clavulanic acid against type I cephases, and synergy is observed for combinations of many penicillins and cephalosporins. Because sulbactam is not well absorbed orally, prodrug forms have been developed. Numerous other penicillin sulfones have been reported to be β‐lactamase inhibitors. Among penam β‐lactamase inhibitors, of 6‐β‐bromopenicillanic acid, a potent inhibitor, has progressed to clinical trials. Although a broad range of β‐lactamase inhibitors has been discovered, only clavulanic acid and sulbactam have been commercialized. Clavulanic acid manufactured by SmithKline Beecham is sold as an oral and parenteral product in combination with amoxicillin under the trade name Augmentin. A parenteral product in combination with ticarcillin, C 15 H 16 N 2 O 6 S, has the trade name, Timentin. The oral version of sulbactam in combination with ampicillin, produced by Pfizer is called Unasyn Oral, which is the mutual prodrug sultamicillin. Two sulbactam parenteral products are sold, a combination product with ampicillin called Unasyn and a combination with cefoperazone called Sulperazon. In addition, sulbactam is sold alone for parenteral use with any β‐lactam antibiotic as Betamaze.

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Comparative Stability of Newly Introduced β-Lactam Antibiotics to Renal Dipeptidase

Abstract: Renal dipeptidase purified from swine kidney hydrolyzed N -formimidoyl thienamycin, carpetimycins A and B, and Sch29482, but not azthreonam, penicillin G, or cephaloridine.

Cited by 19 publications

References 14 publications

Purification and characterization of human renal dehydropeptidase I

Purification and characterization of human renal dehydropeptidase I

In vitro antibacterial activity of Sch 34343 and its stability to beta-lactamases and renal dehydropeptidase 1

β‐Lactamase Inhibitors

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