Post-translational modifications during lantibiotic biosynthesis.

Recent reports have provided the first insights into the mechanisms of the extensive post-translational modifications involved in the biosynthesis of the lantibiotics, a class of peptide antimicrobial agents. These modifications involve dehydration of several serine and threonine residues followed by intramolecular conjugate additions of cysteines, resulting in extensively cross-linked polycyclic structures. Both in vivo and in vitro studies indicate low substrate specificity of the modification machinery, which has been explored for re-engineering of the structures of a number of members. In addition to these developments in understanding their biosynthesis, studies on the mode of action of several lantibiotics have shown a unique mechanism of binding to lipid II, an intermediate in cell wall biosynthesis.

Absorption and metabolism of lanatoside C. II. Fate after oral administration.

The absorption, metabolism, and excretion of lanatoside C were studied in hospitalized subjects following oral administration of the tritiated drug. Previous reports of an unusual double peak in plasma levels of radioactivity were confirmed. Fifty plasma samples taken from 31 patients showed that an average of 74% of the radioactive material was digoxin and its metabolites. There was little or no lanatoside C in 36 of the 50 samples of plasma. Similar results were obtained for urine radioactivity. The results confirm that lanatoside C is converted to "digoxin" in the gut prior to absorption as previously proposed by us. "Digoxin" refers to digoxin and its breakdown products, namely, digoxigenin and its mono- and didigitoxosides. According to these proposals, the conversion to "digoxin" takes place partly as a result of acid hydrolysis in the gut and partly by the action of bacteria in the intestine. The effects of concurrent administration of antacid therapy, anticholinergic therapy, and food on the fate of oral lanatoside C were separately studied. There were no significant differences between groups with respect to the amount of radioactive material absorbed or excreted, but there were marked qualitative differences in the plasma profiles. There was a statistically significant increase in the time to the first peak in plasma radioactivity in patients concurrently receiving either food or anticholinergic therapy and there was a significant decrease in the relative height of the first peak in patients treated concurrently with antacid.

Tissues concentration and excretion of deslanatoside C-3H in newborn and growing rabbits.

Deslanatoside C-3H was injected (i.p. 50 microgram/kg) into rabbits of 1, 4, 10, 20 days and more than 1 year old. The rabbits were sacrificed 2 and 6 h after dosing. Levels in all tissues were higher in newborn rabbits, decreased in the older animals and then in most tissues increased in adults to different degrees, showing the highest values in kidneys. Biliary excretion and above all urinary excretion increased with age. Levels in atria, ventricles, aorta and liver in rabbits 1 and 4 days old were consistently higher at the 6th h than those at the 2nd h, these tissues showing a particularly marked avidity with Deslanatoside C; in the older animals this behaviour was reversed. These data and those of other Authors working on other glycosides (incleding Digoxin) and other species (including newborn children) lead to the conclusion that digitalis glycosides in new born species are excreted at a lower rate and incorporated in the body tissues at a higher rate than in adults. They may also in part explain the large dosages employed in human infants in comparison with adults, as the higher distribtuion volume retains a large amount of the injected glycoside.