Azthreonam (SQ 26,776), a synthetic monobactam specifically active against aerobic gram-negative bacteria

Sykes, R. B.; Bonner, Daniel P.; Bush, Karen; Georgopapadakou, Nafsika H.

doi:10.1128/aac.21.1.85

Cited by 288 publications

(166 citation statements)

References 14 publications

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“…It has targeted activity against aerobic enteric bacteria and P. aeruginosa, with MICs against S. aureus, S. pneumoniae, and E. faecalis !50 mg/mL (Sykes et al 1982). It binds tightly to PBP3 in Gram-negative rods, with weaker binding to PBP1a, leading to filamentation followed by cell lysis (Sykes et al 1982). At the time that it was introduced into clinical practice, aztreonam was stable to hydrolysis by all of the common b-lactamases (Sykes et al 1982); the emergence of ESBLs and the serine carbapenemases has since rendered it less effective against multidrug-resistant blactamase-producing organisms (Wang et al 2014).…”

Section: Monocyclic B-lactamsmentioning

confidence: 99%

“…It binds tightly to PBP3 in Gram-negative rods, with weaker binding to PBP1a, leading to filamentation followed by cell lysis (Sykes et al 1982). At the time that it was introduced into clinical practice, aztreonam was stable to hydrolysis by all of the common b-lactamases (Sykes et al 1982); the emergence of ESBLs and the serine carbapenemases has since rendered it less effective against multidrug-resistant blactamase-producing organisms (Wang et al 2014). However, the monobactam nucleus is not a good substrate for hydrolysis by MBLs, thus leading to a unique opportunity for this monobactam to be used in combination therapy with a serine b-lactamase inhibitor to treat infections caused by multi-b-lactamase-producing bacteria (see below) (Wang et al 2014).…”

Section: Monocyclic B-lactamsmentioning

confidence: 99%

Section: Monocyclic B-lactamsmentioning

confidence: 99%

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β-Lactams and β-Lactamase Inhibitors: An Overview

Bush

Bradford

2016

Cold Spring Harb Perspect Med

707

542

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b-Lactams are the most widely used class of antibiotics. Since the discovery of benzylpenicillin in the 1920s, thousands of new penicillin derivatives and related b-lactam classes of cephalosporins, cephamycins, monobactams, and carbapenems have been discovered. Each new class of b-lactam has been developed either to increase the spectrum of activity to include additional bacterial species or to address specific resistance mechanisms that have arisen in the targeted bacterial population. Resistance to b-lactams is primarily because of bacterially produced b-lactamase enzymes that hydrolyze the b-lactam ring, thereby inactivating the drug. The newest effort to circumvent resistance is the development of novel broad-spectrum b-lactamase inhibitors that work against many problematic b-lactamases, including cephalosporinases and serine-based carbapenemases, which severely limit therapeutic options. This work provides a comprehensive overview of b-lactam antibiotics that are currently in use, as well as a look ahead to several new compounds that are in the development pipeline.

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Section: Monocyclic B-lactamsmentioning

confidence: 99%

Section: Monocyclic B-lactamsmentioning

confidence: 99%

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β-Lactams and β-Lactamase Inhibitors: An Overview

Bush

Bradford

2016

Cold Spring Harb Perspect Med

707

542

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“…Aztreonam, a monobactam (17), has excellent activity against aerobic gram-negative bacteria, especially Enterobacteriaceae (4,16) and Pseudomonas aeruginosa (2,9). Because of its lack of activity against gram-positive and anaerobic organisms, it will likely be used with other agents in the initial therapy of serious infections in appropriate pediatric patients, such as newborns and immunocompromised and post-surgical patients.…”

mentioning

confidence: 99%

In vitro antimicrobial activity of aztreonam alone and in combination against bacterial isolates from pediatric patients

Stutman¹,

Welch²,

Scribner³

et al. 1984

Antimicrob Agents Chemother

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“…Our objective compounds, 3-acylamino-2-azetidinone-l-oxysulfonic acids (12,, were synthesized by the route shown in Schemes 1 and 2. A general synthetic method of f3-lactam from f3-hydroxyl amino acid through cyclization has already been established by MILLER et We modified the method and applied it to the synthesis of 3-tert-butoxycarbonyl-i-hydroxy-2-azetidinones (4).…”

Section: Chemistrymentioning

confidence: 99%

Studies on monocyclic .BETA.-lactam antibiotics. II. Synthesis and antibacterial activity of 3-acylamino-2-azetidinone-1-oxysulfonic acids.

Yoshida¹,

Hori

Momonoi

et al. 1985

J. Antibiot.

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The synthesis and in vitro antibacterial and 13-lactamase inhibitory activity of the 2-azetidinone-l-oxysulfonic acids having a substituent at C-4 position of the p-lactam ring are described. The influence of C-4 substituents on the antibacterial activity was examined for the compounds having a-ureidoacetyl or a-oxyiminoacetyl group as acyl side chain at C-3 position. The antibacterial activity is correlated with the C-4 substituents and acyl side chain. Especially, 4(R)-methyl substituted derivatives exhibited excellent activity against Gram-negative bacteria and 4-dimethyl substituted derivatives exhibited strong activity against resistant Gram-negative bacteria except for Pseudomonas aeruginosa. 39 and 40 showed strong inhibitory activity against cephalosporinase of Enterobacter cloacae H-27.Since the discovery of monocyclic j3-lactam antibiotics represented by nocardicinl' and sulfazecin2,3) and monobactam4,5), many of their derivatives have been reported. As a general characteristic of them, they showed strong activity against Gram-negative bacteria and excellent stability against j3-lactamase. However, they showed weak activity against Gram-positive bacteria. To overcome this insufficiency, various chemical modifications have been tried at N-i, C-3 and C-4 position of (3-lactam. SYKES et al.6,7), and we have independently reported the synthesis and antibacterial activity of the title compounds in a patent literature' . In this paper, we report the chemical modification at C-3 and C-4 position, and the interesting results of antibacterial activity and 3-lactamase inhibitory activity as well. ChemistryOur objective compounds, 3-acylamino-2-azetidinone-l-oxysulfonic acids (12,, were synthesized by the route shown in Schemes 1 and 2. A general synthetic method of f3-lactam from f3-hydroxyl amino acid through cyclization has already been established by MILLER et We modified the method and applied it to the synthesis of 3-tert-butoxycarbonyl-i-hydroxy-2-azetidinones (4).Mixed anhydride of N-Boc-(3-hydroxyamino acids (1) coupled with ethylchloroformate was reacted with O-benzylhydroxylamine to give hydroxamates (2) in good yield. Then, the hydroxamates were cyclized with carbon tetrachloride (CC14)-triphenylphosphine (Ph3P) to give 3-lactams (3). Since optically inactive amino acids were used as starting materials, the obtained /3-lactams (3e ti 3i) were a mixture of two diastereomers. Cis form (3e, 3g, 3j) and traps form (3f, 3h, 3i) were easily isolated by recrystallization or column chromatography on silica gel. However, the cis isomer represented by 3j was not formed in this cyclization reaction. 1-Hydroxy-2-azetidinones (4) were quantitatively ob-

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Azthreonam (SQ 26,776), a synthetic monobactam specifically active against aerobic gram-negative bacteria

Cited by 288 publications

References 14 publications

β-Lactams and β-Lactamase Inhibitors: An Overview

β-Lactams and β-Lactamase Inhibitors: An Overview

In vitro antimicrobial activity of aztreonam alone and in combination against bacterial isolates from pediatric patients

Studies on monocyclic .BETA.-lactam antibiotics. II. Synthesis and antibacterial activity of 3-acylamino-2-azetidinone-1-oxysulfonic acids.

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