O-ACETYLTRANSFERASES FOR CHLORAMPHENICOL AND OTHER NATURAL-PRODUCTS

The range of enzymatic mechanisms by which bacteria inactivate biologi cally active molecules is limited by two kinds of constraint, namely, the structure-activity correlations for each class of chemical agent a nd the metabolic repertoire available to bacteria. In the case of chlo ramphenicol (Cml), which, given its size, has a wealth of vulnerable f unctional groups, there are in principle a number of possibilities. Si nce virtually all the chemical functionalities of Cml (Fig. 1) are kno wn to contribute to its effectiveness as an inhibitor of ribosomal pep tidyltransferase activity (15, 33), it is not surprising that there ha ve been reports of enzyme-mediated resistance to Cml arising from deha logenation, nitro group reduction, and hydrolysis of the amide bond (f or a review, see reference 36) and modification of one or both of the hydroxyls of Cml by phosphorylation (26) and acetylation (36-38). None theless, after more than four decades of medical and veterinary use, t he preponderant enzymatic modification mechanism that has been observe d to underlie Cml resistance in bacteria of clinical importance is tha t of O-acetylation.