Chemical Modification of Pactamycin Leads to New Compounds with Retained Antimicrobial Activity and Reduced Toxicity.

Pactamycin (PCT), an antibiotic produced by , is a five-membered ring aminocyclitol that is active against a variety of Gram-positive and Gram-negative microorganisms, as well as several animal tumor lines in culture and in vivo. Pactamycin targets the small ribosomal subunit and inhibits protein synthesis in bacteria, archaea, and eukaryotes, but due to its toxicity is used only as a tool for biochemical research. Prompted by the successful and well-established procedure for the derivatization of antibiotics, we modified pactamycin by tethering basic amino acids to the free primary amino group of the aminocyclitol ring. Specifically, lysine, ornithine, and histidine were conjugated via an amide bond, and the antimicrobial activity of the derivatives was evaluated both in vivo and in vitro. According to our results, their antimicrobial activity was maintained at almost equal levels, while their toxicity was reduced compared to the parent molecule. These findings suggest that the new pactamycin derivatives can be considered as promising pharmacophores for the development of new antimicrobials that are able to combat the dangerously increasing resistance of pathogens to antibiotics.