β-Lactam Antibiotics: Structure-Activity Relationships

Hoover, John R. E.

doi:10.1007/978-3-642-68901-7_3

Cited by 9 publications

(5 citation statements)

References 286 publications

(185 reference statements)

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“…The carbapenems, because of their broad antibacterial spectra, have become a major focus of pharmaceutical development. So far, some nephrotoxicity is seen with most of the broadly effective penems [3, 5 ± 7, 28], possibly because of their high lactam ring reactivities [2]. A logical method of minimizing renal toxicity would be to develop penems that undergo little or no tubular cell uptake [29].…”

Section: Avoidance Of Toxicitymentioning

confidence: 99%

“…The major beta-lactam groups [penicillins, cephalosporins, and penems ( Fig. 1)] are cyclic dipeptides with two common properties [1,2]: (1) structural homology with bacterial cell wall peptidoglycan precursors; and (2) closure of their dipeptide regions into reactive lactam rings. The dipeptide configuration of the beta-lactams fits the active sites of cell wall-synthesizing bacterial carboxypeptidases.…”

Section: Introductionmentioning

confidence: 99%

“…properties: resistance to beta-lactamases, ability to pass through cell wall porins, affinity for molecular targets, and reactivity or acylating potential [2].…”

Section: Introductionmentioning

confidence: 99%

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Nephrotoxicity of beta-lactam antibiotics: mechanisms and strategies for prevention

Tune

1997

Pediatr Nephrol

124

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The nephrotoxic beta-lactam antibiotics cause acute proximal tubular necrosis. Significant renal toxicity, which has been rare with the penicillins and uncommon with the cephalosporins, is a greater risk with the penems. Mechanisms of injury include: (1) transport into the tubular cell, mainly through the antiluminal organic anion secretory carrier; (2) acylation of target proteins, causing respiratory toxicity by inactivation of mitochondrial anionic substrate carriers; and (3) lipid peroxidation. The most nephrotoxic beta-lactams available for study are cephaloridine, cephaloglycin, and imipenem; panipenem, which is comparably nephrotoxic, is currently available only in Japan. Cephaloridine has several unique properties, probably all caused by its pyridinium side-group: (1) its secretory transport into the tubular cell is followed by minimal cell to luminal fluid movement, resulting in extreme intracellular sequestration; (2) it is the only beta-lactam shown to cause significant oxidative injury; (3) it has a limited ability to attack the mitochondrial carriers for pyruvate and the short-chain fatty anions. Cephaloglycin and imipenem undergo less intracellular trapping than cephaloridine, but have sufficient tubular cell uptake, reactivity, and generalized toxicity to mitochondrial substrate carriers to be severely nephrotoxic. Cephaloridine and cephaloglycin are no longer used clinically. Imipenem and panipenem are marketed in combination with nephroprotective renal transport inhibitors. Strategies for avoiding renal toxicity with new cephalosporins and penems are discussed.

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Section: Avoidance Of Toxicitymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Nephrotoxicity of beta-lactam antibiotics: mechanisms and strategies for prevention

Tune

1997

Pediatr Nephrol

124

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“…It has been suggested (8) that the configuration of the optically active side chains at C-8 influences intrinsic antimicrobial activity and the stereochemistry across C-S to C-6 probably influences both activity and P-lactamase stability or inhibition. The presence of a sulfate at position -8 also appears to enhance ,3-lactamase stability.…”

Section: Structurementioning

confidence: 99%

In vitro and pharmacokinetic properties of the carbapenems

Wise¹

1986

Antimicrob Agents Chemother

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“…First-generation cephalosporins are characterized by Gram-positive bacterial sensitivities that are equivalent to or greater than corresponding penicillins due to their resistance to p-lactamases (Hoover, 1983). Only three commonly available agents of this class can be used for oral administration: cefadroxil, cephalexin and cephradine.…”

mentioning

confidence: 99%