Targeted Nitroxoline Delivery for Treatment of Multidrug-resistant Pathogens
( TANDEM )

Multidrug-resistant pathogens cause approximately 670,000 infections in Europe each year, with an estimated 5% mortality. In the battle against these pathogens, approved anti-infective agents are increasingly ineffective. New strategies for the treatment of infections caused by multidrug-resistant pathogens are urgently needed. Nitroxoline is a highly potent antibiotic drug with broad-spectrum, biofilm-eradicating activities against major human pathogens, including multidrug-resistant strains; however, its clinical use is limited to uncomplicated urinary tract infections due to insufficient organ distribution and cytotoxicity at higher doses. Our aim is to address these shortcomings, and to develop nitroxoline conjugates that allow targeted delivery of the antibiotic to infected tissues. To this end, we will couple nitroxoline to cephalosporin derivatives. The nitroxoline-cephalosporin conjugates (NCCs) are expected to reach sufficient concentrations in human plasma and tissues. Due to the high specificity of cephalosporins for bacterial beta-lactamases, we envisage that nitroxoline is only released once taken up by the pathogen, where it will exert its anti-infective properties, without causing cytotoxic side effects to the host. A library of novel NCCs will be tested against a broad range of bacterial pathogens, and their toxicity profile will be determined. Selected NCCs will be assessed in vivo (mouse) to characterise their pharmacokinetic and pharmacodynamic properties. The strategy is envisaged to be highly translatable to clinical studies.