ChemInform Abstract: MECHANISM OF β‐LACTAM RING OPENING IN CEPHALOSPORINS

Page, Michael I.; Proctor, Philip

doi:10.1002/chin.198440084

Cited by 5 publications

(8 citation statements)

References 1 publication

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“…The Ldt from E. faecium (Ldt fm ) reacts reversibly with nitrocefin, which, unlike most cephalosporins, does not have a C3′ leaving group to drive the reaction forward irreversibly (27). Instead, the C3′ sidechain contains a conjugated chromogen that remains deprotonated, giving a colorimetric signal concurrent with β-lactam scission.…”

Section: Significancementioning

confidence: 99%

Competing off-loading mechanisms of meropenem from an l,d -transpeptidase reduce antibiotic effectiveness

Zandi

Townsend

2021

Proc. Natl. Acad. Sci. U.S.A.

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The carbapenem family of β-lactam antibiotics displays a remarkably broad spectrum of bactericidal activity, exemplified by meropenem’s phase II clinical trial success in patients with pulmonary tuberculosis, a devastating disease for which β-lactam drugs historically have been notoriously ineffective. The discovery and validation of l,d-transpeptidases (Ldts) as critical drug targets of bacterial cell-wall biosynthesis, which are only potently inhibited by the carbapenem and penem structural classes, gave an enzymological basis for the effectiveness of the first antitubercular β-lactams. Decades of study have delineated mechanisms of β-lactam inhibition of their canonical targets, the penicillin-binding proteins; however, open questions remain regarding the mechanisms of Ldt inhibition that underlie programs in drug design, particularly the optimization of kinetic behavior and potency. We have investigated critical features of mycobacterial Ldt inhibition and demonstrate here that the covalent inhibitor meropenem undergoes both reversible reaction and nonhydrolytic off-loading reactions from the cysteine transpeptidase LdtMt2 through a high-energy thioester adduct. Next-generation carbapenem optimization strategies should minimize adduct loss from unproductive mechanisms of Ldt adducts that reduce effective drug concentration.

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Section: Significancementioning

confidence: 99%

Competing off-loading mechanisms of meropenem from an l,d -transpeptidase reduce antibiotic effectiveness

Zandi

Townsend

2021

Proc. Natl. Acad. Sci. U.S.A.

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“…Hal ini disebabkan oleh konsentrasi cincin ß-lactamase di dalam penisilin terhidrolisis oleh basa kuat yaitu dengan cara reaksi nukleofilik [11]. Akan tetapi karena OHpada NaOH sangat kuat daya ikatnya terhadap struktur dalam penisilin, maka serangan OHterhadap cincin ß-lactamase tidak hanya pada gugus keton di cincin ß-lactamase, sebagian OHmenyerang gugus lainnya pada struktur penisilin yang mengakibatkan cincin ß-lactamase dalam air limbah farmasi belum terpecah.kan [12].…”

Section: Hasil Dan Pembahasanunclassified

“…Akan tetapi basa yang digunakan sifatnya basa lemah jadi OHdalam Na2CO3 tidak terionisasi sempurna dalam air, maka serangan OHterhadap gugus keton yang ada di struktur cincin ß-lactamase tidak sebaik basa kuat meskipun serangannya sudah terfokus pada cincin ß-lactamase. Oleh sebab itu OHdalam Na2CO3 kurang kuat dalam menghidrolisis semua cincin ß-lactamase dalam air limbah Betalaktam [12]. Berdasarkan Tabel 4 konsentrasi air limbah Betalaktam setelah penambahan PAC hasilnya cukup konsisten serta penurunannya cukup signifikan, terkecil 0,13 ppm dan terbesar 0,15 ppm.…”

Section: Hasil Dan Pembahasanunclassified

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Pengolahan Air Limbah Betalaktam Menggunakan Reagen Kaporit, PAC, dan Alum Sulfat

Cahyana

Gumilar

Mulyani

2021

JSE

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Beta lactam antibiotics are pollutant in water bodies such as lakes and rivers. Beta lactam rings may have a negative impact on living beings in lakes and rivers. Beta lactam rings also cause resistance or bacterial resistance to antibiotics. If human beings are exposed to beta lactam ring, this could negatively impact on their health. This study attempted to break down the beta lactam rings with several chemical reagents. These reagents hydrolyze the beta lactam ring and are then analyzed using the HPLC (High Performance Liquid Chromatography) instrument. This study aims to determine the how effective the reagent for breaking the beta lactam ring. The research was conducted in three stages: preliminary research, research on reagent effectiveness , and research on β-lactamase degradation using reagents. The results showed that calcium hypochlorite was able to break the beta lactam cycle with 100% efficiency.

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“…Consequently, the substituent attached at the C-3′ position is liberated. [10][11][12][13][14][15][16][17] When the eliminated species possesses antibacterial activity, cephalosporins (4) would exhibit a dual mode of action. [18][19][20] Recently, Albrecht et al [21][22][23] have reported that attachment of antibacterial quinolones to the C-3′ position of cephalosporins gives a class of new compounds with a broadened spectrum of antibacterial activities.…”

Section: Introductionmentioning

confidence: 99%

Cephalosporin 3‘-Phloroglucide Esters and 7-(Phloroglucidamido)cephalosporins as Novel Antibacterial Agents

et al. 1997

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Two series of new phloroglucide derivatives were synthesized that possessed antibacterial activities. The first series includes cephalosporin 3'-phloroglucide esters 19 and 20, which were obtained by condensation of cephalosporin 16 with bioactive phloroglucides 14 and 15, respectively. They exhibited a dual mode of antibacterial action. In comparison with cephalosporins 26 and 27, bearing an acetoxy unit at the C-3' position, the bifunctional cephalosporins 19 and 20 showed a broadened spectrum of activity. Results from the consistent valence force field (CVFF) calculations indicate that the most stable conformational isomer of phenolic acid 14, holding a cis-syn-syn geometry, possessed a cavity. It provides an ideal environment to accommodate metal ions of holoenzymes. Phenolic keto acid 15, however, possessed a trans-anti-syn conformation, which allowed chelation between metal ions and the phenolic hydroxyl groups as well as the carbonyl functionalities. Our biological results show that the cavity formed in phloroglucides plays an important role. The second series includes 7-(phloroglucidamido)cephalosporins 24 and 25, which were synthesized by condensation of cephalosporin 21 with 14 and 15, respectively. Results from the CVFF calculations indicate that cephalosporin 24 also possessed a cavity. Unlike cephalosporin 3'-phloroglucide esters 19 and 20, cephalosporins 24 and 25 were found resistant to beta-lactamases from Staphylococcus aureus 95 and Pseudomonas aeruginosa 18S-H. These new compounds, however, showed notable activities against S. aureus FDA 209P, S. aureus 95, Candida albicans, P. aeruginosa 1101-75, and P. aeruginosa 18S-H.

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ChemInform Abstract: MECHANISM OF β‐LACTAM RING OPENING IN CEPHALOSPORINS

Cited by 5 publications

References 1 publication

Competing off-loading mechanisms of meropenem from an l,d -transpeptidase reduce antibiotic effectiveness

Competing off-loading mechanisms of meropenem from an l,d -transpeptidase reduce antibiotic effectiveness

Pengolahan Air Limbah Betalaktam Menggunakan Reagen Kaporit, PAC, dan Alum Sulfat

Cephalosporin 3‘-Phloroglucide Esters and 7-(Phloroglucidamido)cephalosporins as Novel Antibacterial Agents

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