Targeted Nitroxoline Delivery for Treatment of Multidrug-resistant Pathogens
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.
- Thomas Wichelhaus, Goethe University Frankfurt, Germany (Coordinator)
- Eugen Proschak, Goethe University Frankfurt, Germany (Partner)
- Kerstin Sander, University College London, United Kingdom (Partner)
- Heiko Herwald, Lund University, Sweden (Partner)
Bacteria and other disease-causing organisms that can no longer be controlled or killed with medicines are called multidrug-resistant organisms (MDROs). MDROs pose a major problem to the healthcare system as they can cause severe infections and affect the weakest, in particular young children, the elderly or people with health conditions such as chronic lung, heart, and kidney disease. In Europe, MDROs cause approximately 660,000 infections per year. 35,000 patients do not survive the infection due to the lack of treatment options. Our aim is to develop a much-needed new strategy for the treatment of MDROs. To this end, we have designed a ‘nitroxoline shuttle’. Nitroxoline is an antibiotic drug that effectively kills a broad variety of bacteria; however, its use is limited to bladder infections due to its inability of reaching other parts of the human body. The ‘shuttle’ is a chemical substance that, when linked to nitroxoline, will allow to safely transport this powerful antibiotic to bacteria in various parts of the human body. In the project, we will manufacture the ‘nitroxoline shuttle’ and carry out tests to characterise its ability to kill bacteria in a targeted manner.