Degradation of macrolide antibiotics by ozone: A mechanistic case study with clarithromycin

Macrolide antibiotics are widely used (in the order of 1 g per person per year). They pass the body largely unchanged and are also not degraded in wastewater treatment plants. With not too much effort, they may be eliminated from their effluents by ozonation. The macrolide antibiotics have all a dimethylamino group at one of the carbohydrate residues in common. This functional group is the target of the ozone reaction, and clarithromycin has been selected here for a more detailed study. Since only the free amine reacts with ozone, the rate of reaction is pH dependent (at pH 7: k = 4 × 104 M−1 s−1). In analogy to the ozonolysis of trimethylamine, the main reaction is a transfer of an O-atom yielding the N-oxide (identified by HPLC/MS–MS). A minor product (10%, based on formaldehyde yields) is demethylated clarithromycin (identified by HPLC/MS–MS). The dimethylamino group is thought to be essential for the binding of the macrolide antibiotics to their target. As a consequence, chemical changes of this functional group, notably the formation of the N-oxide that is no longer a proton acceptor, inactivates these drugs as assayed by the suppression of the growth of Pseudomonas putida. This is most important for wastewater treatment, as mineralization of clarithromycin by ozone would require 100 times as much ozone.