MG2-MEDIATED BINDING OF 6-SUBSTITUTED QUINOLONES TO DNA - RELEVANCE TO BIOLOGICAL-ACTIVITY()

The interaction of a number of novel 6-substituted quinolone derivativ es with DNA in the presence/absence of magnesium ions has been investi gated by fluorometric techniques. The drug-single-stranded nucleic aci d interaction is invariantly mediated by the metal ion. In all cases o ptimal complex formation is found at physiological Mg2+ concentration. From titrations at different [Mg2+] the binding constant for the tern ary drug-DNA-Mg2+ complex (K-T) has been evaluated. Interestingly, a g ood relationship is found between K-T and gyrase poisoning activity of the test quinolones (IC50), which confirms that DNA-affinity of the q uinolone, modulated by Mg2+, plays an important role in poisoning the cleavable gyrase-DNA complex and, consequently, in eliciting antibacte rial activity in this family of drugs. The results obtained with diffe rent 6-substituted compounds supports the idea that position 6 of the drug, besides playing a pharmacokinetic role, is involved in recogniti on of the enzyme pocket. Our data do not support a mechanism of action based upon quinolone intercalation into B-DNA. (C) 1998 Elsevier Scie nce Ltd. All rights reserved.