Mechanism of .beta.-lactam ring opening in cephalosporins

Page, Michael I.; Proctor, Philip

doi:10.1021/ja00325a019

Cited by 59 publications

(32 citation statements)

References 2 publications

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“…The situation is less favorable for the cephalosporins since the three drugs we tested here (and which probably represent the most useful ones in cases of severe infections) showed significantly less stability than penicillins. Chemical considerations suggest that cephalosporins are more reactive than penicillins, and thus less stable in water basedmedia, because of their C3 substituent, which acts as a leaving group (4, 5) (this hypothesis has, however, been challenged [26]). Since the C3 substituents of ceftazidime, cefepime, and cefpirome (a pyridinium, a pyrrolidinium, and a 5H-cyclopentapyridinium, respectively) are all cationic, a common behavior of these molecules with respect to stability is not surprising.…”

Section: Discussionmentioning

confidence: 99%

Comparative Stability Studies of Antipseudomonal β-Lactams for Potential Administration through Portable Elastomeric Pumps (Home Therapy for Cystic Fibrosis Patients) and Motor-Operated Syringes (Intensive Care Units)

Viaene

Chanteux

Servais

et al. 2002

Antimicrob Agents Chemother

173

123

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The stability of antipseudomonal ␤-lactams in concentrated solutions was examined in view of their potential administration by continuous infusion with external pumps (for intensive care patients) or with portable pumps carried under clothing (for cystic fibrosis patients). Aztreonam (100 g/liter), piperacillin (128 g/liter, with tazobactam), and azlocillin (128 g/liter) remained 90% stable for up to more than 24 h at 37°C (mezlocillin [128 g/liter] was stable at 25°C but not at 37°C). Ceftazidime (120 g/liter), cefpirome (32 g/liter), and cefepime (50 g/liter) remained 90% stable for up to 24, 23.7, and 20.5 h at 25°C but only for 8, 7.25, and 13 h at 37°C, respectively. The control of temperature therefore appears to be critical for all three cephalosporins that cannot be recommended for use in portable pumps carried under clothes for prolonged periods for reasons of stability. Cefpirome and cefepime solutions developed an important color change (from light yellow to dark red) upon exposure when stored at 30°C or higher. Degradation of ceftazidime was accompanied by the liberation of pyridine which, at 37°C, was in excess of what is allowed by the U.S. Pharmacopeia, i.e., 1.1 mg/liter, after 8 and 12 h for drug concentrations of 12 and 8.3%, respectively. Imipenem and meropenem are too unstable (10% degradation at 25°C after 3.5 and 5.15 h, respectively) to be recommended for use by continuous infusion. Faropenem, examined in comparison with imipenem and meropenem, proved as stable as aztreonam or piperacillin.␤-Lactams are one of the most typical antibiotic classes for which the pharmacodynamic data, collected in vitro, as well as in animal studies, clearly indicate a potential advantage of a continuous infusion over the more conventional, discrete mode of administration (see references 6, 22, 23, 38, and 41 for reviews). Accordingly, several clinical trials have been initiated over the last half-decade, most notably in difficult-to-treat situations such as suspected gram-negative infections in critically ill patients (3), severe infections in intensive care patients (8,16,21,24,37), septicemia (1), severe sepsis (20), and cystic fibrosis (29,40). Yet, as clearly pointed out by one of the first promoters of the continuous infusion of ␤-lactams (6), this mode of administration, through programmable pumps or other similar devices, requires the drug to remain sufficiently stable in solution over the projected duration of the infusion. In a previous study (30), we examined the stability of ceftazidime in solution and found it to be critically dependent on the temperature within the 20 to 37°C range (68 to 99°F). This sets clear limitations on the potential use of ceftazidime by continuous infusion if administrations every 24 h are contemplated without periodic changes of the solutions. Chemical considerations suggest that the stability of the main ␤-lactams currently registered for human medicine use may vary to a meaningful extent. Unfortunately, these variations, and their consequences as far as continuous infu...

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Section: Discussionmentioning

confidence: 99%

Comparative Stability Studies of Antipseudomonal β-Lactams for Potential Administration through Portable Elastomeric Pumps (Home Therapy for Cystic Fibrosis Patients) and Motor-Operated Syringes (Intensive Care Units)

Viaene

Chanteux

Servais

et al. 2002

Antimicrob Agents Chemother

173

123

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“…Cefsulodin and cephaloridine have a C3Ј pyridinium moiety that acts as a leaving group during acylation similar to the CENTA TNB group. It is well established that the C3Ј moiety can have a profound influence on acylation rates by delocalizing electrons from the former lactam nitrogen either by acting as an electron withdrawing substituent or leaving group during lactam bond fission (41,42). Therefore, the presence of a good C3Ј leaving group is an important feature to consider when designing cephalosporin-based inhibitors of E. coli PBP1b.…”

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confidence: 99%

Structural Insights into Inhibition of Escherichia coli Penicillin-binding Protein 1B

King

Wasney

Nosella

et al. 2017

Journal of Biological Chemistry

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Edited by F. Peter GuengerichIn Escherichia coli, the peptidoglycan cell wall is synthesized by bifunctional penicillin-binding proteins such as PBP1b that have both transpeptidase and transglycosylase activities. The PBP1b transpeptidase domain is a major target of ␤-lactams, and therefore it is important to attain a detailed understanding of its inhibition. The peptidoglycan glycosyltransferase domain of PBP1b is also considered an excellent antibiotic target yet is not exploited by any clinically approved antibacterials. Herein, we adapt a pyrophosphate sensor assay to monitor PBP1b-catalyzed glycosyltransfer and present an improved crystallographic model for inhibition of the PBP1b glycosyltransferase domain by the potent substrate analog moenomycin. We elucidate the structure of a previously disordered region in the glycosyltransferase active site and discuss its implications with regards to peptidoglycan polymerization. Furthermore, we solve the crystal structures of E. coli PBP1b bound to multiple different ␤-lactams in the transpeptidase active site and complement these data with gel-based competition assays to provide a detailed structural understanding of its inhibition. Taken together, these biochemical and structural data allow us to propose new insights into inhibition of both enzymatic domains in PBP1b.

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“…The general kinetic Scheme 4 can be suggested for the aminolysis of oxazolinones 1a, 1b and 1f; it can formally be identified with that of aminolysis of -lactams. [16][17][18][19] The first reaction step involves addition of amine to the carbonyl group of oxazoline giving the tetrahedral zwitterionic intermediate In AE . Generally, the decomposition of the intermediate can be assisted by the basic or acidic buffer component, or the intermediate can decompose spontaneously and very rapidly in a non-catalysed way.…”

Section: Aminolysismentioning

confidence: 99%

Steric and electronic substituent effects in hydrolysis and aminolysis of 4‐alkyl‐4‐methyl‐2‐aryl‐4,5‐dihydro‐1,3‐oxazol‐5‐ones

Sedlák

Keder

Skála

et al. 2005

J of Physical Organic Chem

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The kinetics and mechanism of the acid-catalysed hydrolysis of substituted 4-alkyl-4-methyl-2-aryl-4,5-dihydro-1,3-oxazol-5-ones to the corresponding 2-alkyl-2-benzoylaminopropanoic acids were studied. The Taft correlation of rate constants of the acid-catalysed hydrolysis with alkyl substitution at the 4-position of the 1,3-oxazol-5-one ring is non-linear. In the Hammett correlation, the value of decreases with increasing steric demand of the alkyl substituent. With the 4-isopropyl and tert-butyl derivatives, ¼ À0.63 and À0.32, respectively. The protonated 4-isopropyl and tert-butyl derivatives undergo nucleophilic attack by water at the carbonyl carbon atom at the 5position of the 1,3-oxazol-5-one ring to the extents of ca 70% and 60%, respectively. Another reaction path consists in nucleophilic attack by water at the 2-position of the 1,3-oxazol-5-one ring. The reaction kinetics of aminolyses of substituted 4-isopropyl-4-methyl-2-phenyl-1,3-oxazol-5(4H)-ones (1a, 1b, 1f) giving substituted N-{1,2-dimethyl-1-[(propylamino)carbonyl]-propyl}benzamides (3a, 3b, 3f, 4a) was studied in aqueous propylamine buffers. In the case of the aminolysis of 1a and 1b with propylamine, the rate-limiting step consists in the decomposition of the intermediate In AE catalysed by both the acidic and the basic buffer components. The base-catalysed route is four times faster in both cases. In the case of the aminolysis of 1f with propylamine and that of 1a with ethylenediamine, the ratelimiting step is the formation of the intermediate In AE , the subsequent reaction step being accelerated by substitution and/or intramolecular catalysis. EXPERIMENTAL MaterialsThe new dialkyl-2-aryl-4,5-dihydro-1,3-oxazol-5-ones were prepared by a known method 11 of ring closure and

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Mechanism of .beta.-lactam ring opening in cephalosporins

Cited by 59 publications

References 2 publications

Comparative Stability Studies of Antipseudomonal β-Lactams for Potential Administration through Portable Elastomeric Pumps (Home Therapy for Cystic Fibrosis Patients) and Motor-Operated Syringes (Intensive Care Units)

Comparative Stability Studies of Antipseudomonal β-Lactams for Potential Administration through Portable Elastomeric Pumps (Home Therapy for Cystic Fibrosis Patients) and Motor-Operated Syringes (Intensive Care Units)

Structural Insights into Inhibition of Escherichia coli Penicillin-binding Protein 1B

Steric and electronic substituent effects in hydrolysis and aminolysis of 4‐alkyl‐4‐methyl‐2‐aryl‐4,5‐dihydro‐1,3‐oxazol‐5‐ones

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