Design and synthesis of water-soluble prodrugs of rifabutin for intraveneous administration

Acinetobacter baumannii is a gram-negative bacterium causing severe hospital-acquired infections such as bloodstream infections or pneumonia. Moreover, multidrug resistant A. baumannii becomes prevalent in many hospitals. Consequently, the World Health Organization made this bacterium a critical priority for the research and development of new antibiotics. Rifabutin, a semisynthetic product from the rifamycin class, was recently found to be very active in nutrient-limited eukaryotic cell culture medium against various A. baumannii strains, including extremely drug-resistant strains, with minimal inhibitory concentrations as low as 0.008 μg/mL. Moreover, this in vitro potency translates into in vivo efficacy. Thus, rifabutin appears to be an attractive novel antibiotic against A. baumannii. In this work, our objective was to design and synthetize rifabutin prodrugs with increased aqueous solubility to allow intraveneous use. Synthetic methodologies were developed to selectively functionalize the hydroxyl group in position 21 and to afford 17 prodrugs. We measured the water solubility of the prodrugs, the stability in human and mouse plasma and their antimicrobial activity against A. baumannii after incubation in human serum. Finally, a pharmacokinetic release study of rifabutin was performed in CD1 mice with three selected prodrugs as a proof of concept.