Synthesis and antibacterial activity of new C-10 quinolonyl-cephem esters.

Demuth, Thomas P.; White, Ronald E.; Tietjen, Ronald; Storrin, R. J.; Skuster, James R.; Andersen, Jon; McOsker, Charles C.; Freedman, R.; Rourke, F. James

doi:10.7164/antibiotics.44.200

Cited by 22 publications

(11 citation statements)

References 17 publications

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“…67−69 Iodination at the 3′-position with TMSI gave the activated iodocephalosporin 30 ready for coupling. 36 The ciprofloxacin component was prepared by BOC protection of the piperazine NH to give 32 and subsequent conversion of the carboxylic acid to the sodium salt 33 . 70 Coupling of compounds 30 and 33 was performed in 3:1 1,4-dioxane/DMF to give the protected cephalosporin–ciprofloxacin conjugate 34 .…”

Section: Resultsmentioning

confidence: 99%

“… − Additionally, β-lactam–fluoroquinolone conjugates have been proposed as a co-drug strategy to treat bacterial infections ( 4 and 5 , Figure ). − However, our approach is different in that it is designed to selectively deliver a broad-spectrum, bactericidal antibiotic to only bacteria that express β-lactamase, while having minimal effect on bacteria that do not express the resistance determinant. By contrast, previous dual activity co-drug approaches were designed to have broad-spectrum activity against both drug-sensitive bacteria and those that express β-lactamase.…”

Section: Introductionmentioning

confidence: 99%

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Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a β-Lactamase-Activated Antibacterial Prodrug

Evans

Krishna

et al. 2019

J. Med. Chem.

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Expression of β-lactamase is the single most prevalent determinant of antibiotic resistance, rendering bacteria resistant to β-lactam antibiotics. In this article, we describe the development of an antibiotic prodrug that combines ciprofloxacin with a β-lactamase-cleavable motif. The prodrug is only bactericidal after activation by β-lactamase. Bactericidal activity comparable to ciprofloxacin is demonstrated against clinically relevant E. coli isolates expressing diverse β-lactamases; bactericidal activity was not observed in strains without β-lactamase. These findings demonstrate that it is possible to exploit antibiotic resistance to selectively target β-lactamase-producing bacteria using our prodrug approach, without adversely affecting bacteria that do not produce β-lactamase. This paves the way for selective targeting of drug-resistant pathogens without disrupting or selecting for resistance within the microbiota, reducing the rate of secondary infections and subsequent antibiotic use.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a β-Lactamase-Activated Antibacterial Prodrug

Evans

Krishna

et al. 2019

J. Med. Chem.

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“…In recent years, a number of compounds which consist of a cephalosporin covalently linked at the 3' position to a quinolone via an ester, carbamate, or tertiary amine linkage have been synthesized (1)(2)(3)5). These compounds have a dual mechanism of action (hence the name dual-action cephalosporins [DACs]), reflecting the actions of both the f3-lactam and the quinolone components; they bind to penicillin-binding proteins and inhibit DNA gyrase (1-3, 10, 18).…”

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confidence: 99%

beta-Lactamase hydrolysis of cephalosporin 3'-quinolone esters, carbamates, and tertiary amines

Georgopapadakou

McCaffrey

1994

Antimicrob Agents Chemother

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The ,-lactam hydrolysis of five cephalosporin 3'-quinolones (dual-action cephalosporins) by three gramnegative P-lactamases was examined. The dual-action cephalosporins tested were the ester Ro 23-9424; the carbamates Ro 25-2016, Ro 25-4095, and Ro 25-4835; and the tertiary amine Ro 25-0534. Also tested were cephalosporins with similar side chains (cefotaxime, desacetylcefotaxime, cephalothin, cephacetrile, and Ro 09-1227 [SR 0124]) and standard P-lactams (penicillin G, cephaloridine). The ,-lactamases used were the plasmid-mediated TEM-1 and TEM-3 enzymes and the chromosomal AmpC. The cephacetrile-related compounds Ro 25-4095 and Ro 25-4835 were hydrolyzed by all three P-lactamases with catalytic efficiencies (relative to penicillin G) ranging from -5 (TEM-1, AmpC) to -25 (TEM-3). The cephalothin-related Ro 25-2016 was also hydrolyzed by all three I-lactamases, particularly the AmpC enzyme (relative catalytic efficiency, 110). The cefotaxime-related compounds Ro 25-0534 and Ro 23-9424 were hydrolyzed to any significant extent only by the TEM-3 enzyme (relative catalytic efficiencies, 1.2 and 4.7, respectively).In recent years, a number of compounds which consist of a cephalosporin covalently linked at the 3' position to a quinolone via an ester, carbamate, or tertiary amine linkage have been synthesized (1-3, 5). These compounds have a dual mechanism of action (hence the name dual-action cephalosporins [DACs]), reflecting the actions of both the f3-lactam and the quinolone components; they bind to penicillin-binding proteins and inhibit DNA gyrase (1-3, 10, 18). In growing Escherichia coli devoid of ,B-lactamase, the esters act as cephalosporins when intact, while the carbamates and tertiary amines act primarily as quinolones (8, 9).Theoretically, cephalosporin 3'-quinolones may release free quinolone directly, by hydrolysis of the cephalosporin-quinolone linkage, or indirectly, subsequent to opening of the ,B-lactam ring (6,14). The former reaction is chemical, while the latter reaction is enzymatic and is catalyzed primarily by ,B-lactamases. In the study described in this report, we examined the hydrolysis of cephalosporin 3'-quinolones and reference compounds by three gram-negative ,B-lactamases. The first, TEM-1, is plasmid mediated and is the most common ,B-lactamase in gram-negative bacteria. The second, TEM-3, is a cefotaxime-hydrolyzing enzyme derived from TEM-2 (itself a variant of TEM-1). The third, AmpC, is a chromosomally encoded ,B-lactamase similar to those responsible for 1-lactam resistance in Enterobacter cloacae and Pseudomonas aeruginosa. ,B-Lactam hydrolysis of the cephalosporin 3'-quinolones by any of the three enzymes would be expected to release free quinolone (14).MATERUILS AND METHODS Chemicals. Bovine serum albumin (BSA), egg white lysozyme, EDTA, and Trizma base were obtained from Sigma Chemical Co. (St. Louis, Mo.); DEAE cellulose (DE-52) and carboxymethyl cellulose (CM-52) were from Pharmacia LKB Biotechnology (Piscataway, N.J.); potassium and potassium iodide were from Fisher Scie...

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“…Hybrids of cephalosporins, carbapenems, or penems with fluoroquinolones have been extensively studied by Roche [94–96] . Of the β‐lactam‐fluoroquinolone hybrids generated, a compound termed Ro 23‐9424 (Figure 7) was the most promising with high potency in vitro against Gram‐positive as well as Gram‐negative strains including strains resistant to either one or both parent antibiotics [97,98] .…”

Section: Introductionmentioning

confidence: 99%

Fresh Molecular Concepts to Extend the Lifetimes of Old Antimicrobial Drugs

Jaber

Fridman

2021

The Chemical Record

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Antimicrobial drug development generally initiates with target identification and mode of action studies. Often, emergence of resistance and/or undesired side effects that are discovered only after prolonged clinical use, result in discontinuation of clinical use. Since the cost and time required for improvement of existing drugs are considerably lower than those required for the development of novel drugs, academic and pharmaceutical company researchers pursue this direction. In this account we describe selected examples of how chemical probes generated from antimicrobial drugs and chemical and enzymatic modifications of these drugs have been used to modify modes of action, block mechanisms of resistance, or reduce side effects, improving performance. These examples demonstrate how new and comprehensive mechanistic insights can be translated into fresh concepts for development of next‐generation antimicrobial agents.

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Synthesis and antibacterial activity of new C-10 quinolonyl-cephem esters.

Cited by 22 publications

References 17 publications

Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a β-Lactamase-Activated Antibacterial Prodrug

Exploitation of Antibiotic Resistance as a Novel Drug Target: Development of a β-Lactamase-Activated Antibacterial Prodrug

beta-Lactamase hydrolysis of cephalosporin 3'-quinolone esters, carbamates, and tertiary amines

Fresh Molecular Concepts to Extend the Lifetimes of Old Antimicrobial Drugs

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