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KMID : 0370219960400010102
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Yakhak Hoeji
1996 Volume.40 No. 1 p.102 ~ p.111
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Action Mechanism of LB10522, a New Catechol-Substituted Cephalosporin
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김무용/Kim MY
오정인/백경숙/김인철/곽진환/Oh JI/Paek KS/Kim IC/Kwak JH
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Abstract
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LB10522 is a new parenteral broad spectrum cephalosporin with a catechol moiety at C-7 position of beta-lactam ring. This compound can utilize tonB-dependent iron transport system in addition to porin proteins to enter bacteria] periplasmic space and access to penicillin-binding proteins (PBPs) which are the lethal targets of beta-lactam antibiotics. The chelating activity of LB10522 to metal iron was measured by spectrophotometrically scanning the absorbance from 200 to 900nm. When FeCl3 was added, optical density was increased between 450 and 800nm. LB10522 was more active against gram-negative strains in iron-depleted media than in iron-replete media. This is due to the increased expression of iron transport channels in iron-depleted condition. LB10522 showed a similar activity against E. coli DC2 (permeability mutant) and E. coli DCO (wild type strain) in both iron-depleted and iron-replete media, indicating a minimal permeaility barrier for LB10522 uptake. LB10522 had high affinities to PBP 3 and PBP 1A, 1B of E. coli. By blocking these proteins, LB10522 caused inhibition of cell division and the eventual death of cells. This result was correlated well with the morphological changes in E. coli exposed to LB10522. Although the in vitro MIC of LB10522 against P. aeruginosa 1912E mutant (tonB) was 8-times higher than that of the P. aeruginosa 1912E parent strain, LB10522 showed a similar in vivo protection efficacy against both strains in the mouse systemic infection model. This result suggested that tonB mutant, which requires a high level of iron for normal growth, might have a difficulty in surviving in their host with an iron-limited environment.
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