Reference

Mechanism of action of nalidixic acid: Purification of Escherichia coli nalA gene product and its relationship to DNA gyrase and a novel nicking-closing enzyme

Mechanism of action of nalidixic acid: Purification of Escherichia coli nalA gene product and its relationship to DNA gyrase and a novel nicking-closing enzyme. Sugino, Akio; Peebles, Craig L.; Kreuzer, Kenneth N.; Cozzarelli, Nicholas R. (Dep. Biochem., Univ. Chicago, Chicago, Ill., USA). Proc. Natl. Acad. Sci. U. S. A., 74(11), 4767-71 (English) 1977. CODEN: PNASA6. DOCUMENT TYPE: Journal CA Section: 3 (Biochemical Interactions) Section cross-reference(s): 6 A target protein for nalidixic acid (I) [389-08-2] and oxolinic acid [14698-29-4] in E. coli, the na1A gene product (Pnal), was purified to homogeneity as judged by gel electrophoresis, using an in vitro complementation assay. It is a dimer of identical 110,000-dalton subunits. I and oxolinic acid inhibited DNA gyrase activity and induced formation of a relaxation complex analog. Treatment of the complex with Na dodecyl sulfate caused a double-strand break in the DNA substrate and the resulting linear mol. seemed covalently bound to protein. Complex formation, unlike the introduction of supertwists, did not require ATP or relaxed circular DNA and was insensitive to novobiocin. DNA gyrase from a strain with na1A mutation conferring drug resistance (na1Ar) was 1/100 as sensitive to oxolinic acid and I with respect to inhibition of supertwisting and induction of the prelinearization complex. Addn. of Pnal restored drug sensitivity and stimulated DNA gyrase activity. DNA gyrase prepns. and Pnal catalyzed a 3rd reaction sensitive to I and oxolinic acid, the ATP-independent relaxation of supertwisted DNA. Relaxation by gyrase from na1Ar cells was drug resistant. The nicking-closing activity was distinct from E. coli w protein in several properties, including the ability to relax pos. supertwisted DNA. The na1A gene product may occur in 2 mol. forms, as Pnal and as a gyrase component. Both forms catalyze nicking-closing, and inhibition of this activity by I and oxolinic acid may account for the inhibition of DNA synthesis by these drugs.

Arthropathy induced by antibacterial fused N-alkyl-4-pyridone-3-carboxylic acids

Arthropathy induced by antibacterial fused N-alkyl-4-pyridone-3-carboxylic acids. Ingham, B.; Brentnall, D. W.; Dale, Eugenie A.; McFadzean, J. A. (May and Baker Ltd., Dagenham/Essex, Engl.). Toxicol. Lett., 1(1), 21-6 (English) 1977. CODEN: TOLED5. DOCUMENT TYPE: Journal CA Section: 1 (Pharmacodynamics) The antibacterial agents, nalidixic acid [389-08-2], oxolinic acid [14698-29-4], and pipemidic acid (I) [51940-44-4], induced lameness, assocd. with exudation of synovial fluid and blistering and ulcerative erosion of articular cartilage, in the joints of the limbs of immature, but not mature, dogs when administered daily, for periods of 1-15 days, at dose rates of 200-1000 mg/kg. Clin. recovery usually occurred within 14-21 days, even with continued medication, but the lesions had not resolved in animals autopsied up to 87 days after withdrawal of the drug. The lesions were also present at autopsy in immature dogs which had received I daily for 6 mo, in spite of the fact that the animals had been clin. normal for all except the 1st 4 or 5 wk of the study. Microscopic examn. showed that fissuring occurred in the intermediate, germinal zone of cartilage. Hypertrophy of chondrocytes was a common finding, with some large cell nests and multinucleate cells. In a few cases, some disorganization of epiphyseal plates was seen.