Exploring the chemistry of penicillin as a β-lactamase-dependent prodrug

Ruddle, Carol C.; Smyth, Timothy P.

doi:10.1039/b614758e

Cited by 16 publications

(7 citation statements)

References 28 publications

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“…30, 31 In the case of cephalosporins, scission of the β-lactam ring triggers elimination of the 3’-substituent. 32, 33 A variety of cephalosporin analogs have been designed to take advantage of this reactivity to release bioactive molecules, including quinolones, halogenated dipeptides, thiols, umbelliferone, 5-fluorouracil, and others. 34 – 43 In particular, O’Callaghan et al 44 explored the antibacterial activity of a cephalosporin that released pyrithione (PT), a metal-chelating agent with excellent broad-spectrum antibacterial and antifungal activity that synergizes with Cu to induce toxicity.…”

Section: Resultsmentioning

confidence: 99%

“…The β-lactamase enzymes produced by antibiotic-resistant bacteria hydrolyze β-lactam rings to render such drugs ineffective at inhibiting their intended targets: penicillin-binding proteins, which are central to bacterial cell wall biosynthesis. , In the case of cephalosporins, scission of the β-lactam ring triggers elimination of the 3′-substituent. , A variety of cephalosporin analogs have been designed to take advantage of this reactivity to release bioactive molecules, including quinolones, halogenated dipeptides, thiols, umbelliferone, 5-fluorouracil, and others. − In particular, O’Callaghan et al explored the antibacterial activity of a cephalosporin that released pyrithione (PT), a metal-chelating agent with excellent broad-spectrum antibacterial and antifungal activity that synergizes with Cu to induce toxicity. − We utilized a similar PT-releasing molecule, PcephPT, for our studies on the metal-dependent antibacterial mode of action of β-lactamase-activated prochelators. We hypothesized that attaching PT to a cephalosporin at one of its metal-chelating atoms would greatly reduce its metal affinity prior to enzymatic activation.…”

Section: Resultsmentioning

confidence: 99%

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Copper Influences the Antibacterial Outcomes of a β-Lactamase-Activated Prochelator against Drug-Resistant Bacteria

et al. 2018

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The unabated rise in bacterial resistance to conventional antibiotics, coupled with collateral damage to normal flora incurred by overuse of broad-spectrum antibiotics, necessitates the development of new antimicrobials targeted against pathogenic organisms. Here, we explore the antibacterial outcomes and mode of action of a prochelator that exploits the production of β-lactamase enzymes by drug-resistant bacteria to convert a nontoxic compound into a metal-binding antimicrobial agent directly within the microenvironment of pathogenic organisms. Compound PcephPT (phenylacetamido-cephem-pyrithione) contains a cephalosporin core linked to 2-mercaptopyridine N-oxide (pyrithione) via one of its metal-chelating atoms, which minimizes its preactivation interaction with metal ions and its cytotoxicity. Spectroscopic and chromatographic assays indicate that PcephPT releases pyrithione in the presence of β-lactamase-producing bacteria. The prochelator shows enhanced antibacterial activity against strains expressing β-lactamases, with bactericidal efficacy improved by the presence of low-micromolar copper in the growth medium. Metal analysis shows that cell-associated copper accumulation by the prochelator is significantly lower than that induced by pyrithione itself, suggesting that the location of pyrithione release influences biological outcomes. Low-micromolar (4-8 μg/mL) minimum inhibitory concentration (MIC) values of PcephPT in ceftriaxone-resistant bacteria compared with median lethal dose (LD) values greater than 250 μM in mammalian cells suggests favorable selectivity. Further investigation into the mechanisms of prochelators will provide insight for the design of new antibacterial agents that manipulate cellular metallobiology as a strategy against infection.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Copper Influences the Antibacterial Outcomes of a β-Lactamase-Activated Prochelator against Drug-Resistant Bacteria

et al. 2018

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“…Other natural enzymes have also been proposed, studied, and applied. For example, lactamase-responsive prodrugs , hydrogel biomaterials , and imaging probes have all been reported. Another good example is transglutaminase, a type of enzyme usually found at the site of tissue healing and blood coagulation.…”

Section: Conclusion and Prospectsmentioning

confidence: 99%

Proteolysis: A Biological Process Adapted in Drug Delivery, Therapy, and Imaging

2009

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In many diseases, protease expressions are found deregulated when compared with them at the healthy states. The unique ability to hydrolyze protein amide bonds has made those deregulated proteases attractive biological triggers in drug development. Proteolysis has been widely applied in pro-drug design to achieve favorable pharmacokinetics. Controlled drug delivery systems are also reported by incorporating protease-sensitive motifs onto bio-, inorganic-, or organic- materials. In addition, protease responsive molecular probes are developed for in vitro bioanalysis and in vivo diagnostic imaging. This review focuses on various proteolysis-dependent approaches to drug delivery, therapy, and imaging. References are selected to illustrate the concepts and demonstrate the potentials of these enzyme-responsive strategies.

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“…Attachment of 7-hydroxy-4-methylcoumarin as the releasable group of this side chain generates a penicillin structure that can function as a fluorescence-based reporter substance/diagnostic for the presence of low levels of b-lactamase enzyme in solution [204].…”

Section: Hydrolysismentioning

confidence: 99%

The Chemistry of 2‐Azetidinones (β‐Lactams)

Alcaide¹,

Almendros²,

Luna³

2011

Modern Heterocyclic Chemistry

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The large number of recent reports on b-lactam chemistry demonstrates the increasing interest in this important class of compounds. Monocyclic b-lactams frequently serve as precursors for the synthesis of classical bicyclic b-lactam antibiotics. The cyclic 2-azetidinone skeleton has been extensively used as a template on which to build the heterocyclic structure fused to the four-membered ring, using the chirality and functionalization of the b-lactam nucleus as a stereocontrolling element. The discovery of nonclassical b-lactam antibiotics, such as monobactams and nocardicins, coupled with ever-growing new applications such as enzyme inhibition has triggered a renewed interest in the building of new monocyclic b-lactam derivatives. Besides the utility of b-lactams as biologically active agents, they are used as intermediates in a-and b-amino acid synthesis, as well as building blocks for alkaloids, heterocycles, taxoids and other types of compounds of biological and medicinal interest. Physicochemical Data Computational ChemistryTheoretical studies show that b-lactams are weaker bases, in the gas phase, than acyclic amides [1]. The attenuation of basicity upon cyclization is stronger than that found for cyclic ketones of similar size due to the existence of a negative hyperconjugation effect that is present in b-lactams but not in cyclic ketones. Ab initio calculations indicate that both b-lactams and acyclic amides are oxygen bases, but the gap between the oxygen and nitrogen intrinsic basicities is much smaller in the former due to the aforementioned cyclization effects. This decrease of the oxygen Modern Heterocyclic Chemistry, First Edition. Edited

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Exploring the chemistry of penicillin as a β-lactamase-dependent prodrug

Cited by 16 publications

References 28 publications

Copper Influences the Antibacterial Outcomes of a β-Lactamase-Activated Prochelator against Drug-Resistant Bacteria

Copper Influences the Antibacterial Outcomes of a β-Lactamase-Activated Prochelator against Drug-Resistant Bacteria

Proteolysis: A Biological Process Adapted in Drug Delivery, Therapy, and Imaging

The Chemistry of 2‐Azetidinones (β‐Lactams)

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