Interaction of divalent cations, quinolones and bacteria.
The interaction between divalent cations and quinolones and the mechanism by which the former antagonizes the antimicrobial activities of the latter were investigated. In the presence of either magnesium or calcium chloride, the MICs of 18 quinolones for Gram-positive and Gram-negative bacteria increased. Accumulation of and inhibition of DNA synthesis by quinolones were decreased in the presence of magnesium chloride while, in the presence of EDTA, there was no increase in the concentration of accumulated quinolone for any of the agents tested. Only with nalidixic acid was there enhancement of the inhibition of DNA synthesis. Chelation of selected quinolones by magnesium was demonstrated with a fluorescence assay which showed that the extent to which fluorescence (consistent with chelation) was enhanced varied with the quinolone. Assessment of the strength of the magnesium-quinolone complexes with the chelating agent EDTA demonstrated that some of the complexes could be broken. Thin layer chromatography of quinolones and quinolone-magnesium complexes provided evidence that the components of the complex were probably combined in a ratio of 1:1 and that reduced intracellular accumulation of the quinolones in the presence of magnesium was unlikely to be due to a complex being too bulky to be taken through the porin channels. In contrast with permeabilizers which are known to utilize the self-promoted uptake pathway, none of the quinolones studied permeabilized Gram-negative bacteria to lysozyme, caused enhanced fluorescence to 1-N-phenyl-naphthylamine (NPN) or increased the leakage of periplasmic beta-lactamase into the culture medium. The reduced activities of the quinolones in the presence of divalent cations may be the result of the chelation of exogenous ions and, possibly, lipopolysaccharide- or lipoteichoic acid-associated magnesium ions, thereby resulting in less drug being available to enter the bacterium. Alternatively, reduced activity may be due to a fundamental effect on the interaction between quinolones and their target DNA gyrase.
Marshall
A J
AJ
Department of Infection, Medical School, University of Birmingham, UK.
Piddock
L J
LJ
D042462:4-Quinolones; D000890:Anti-Infective Agents / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D001419:Bacteria / Q000187:drug effects* / Q000648:ultrastructure; D001425:Bacterial Outer Membrane Proteins / Q000378:metabolism; D002118:Calcium / Q000494:pharmacology; D002413:Cations, Divalent / Q000494:pharmacology*; D002462:Cell Membrane / Q000378:metabolism; D002614:Chelating Agents / Q000494:pharmacology; D002855:Chromatography, Thin Layer; D003470:Culture Media; D004269:DNA, Bacterial / Q000096:biosynthesis; D004492:Edetic Acid / Q000494:pharmacology; D005453:Fluorescence; D008274:Magnesium / Q000494:pharmacology; D011113:Polymyxins / Q000494:pharmacology
D042462:4-Quinolones; D000890:Anti-Infective Agents; D001425:Bacterial Outer Membrane Proteins; D002413:Cations, Divalent; D002614:Chelating Agents; D003470:Culture Media; D004269:DNA, Bacterial; D011113:Polymyxins; D004492:Edetic Acid; D008274:Magnesium; D002118:Calcium