Polymeric Cyclodextrin-Based Supramolecular Constructs Photoreleasing Nitric Oxide for Combating Antibiotic Resistance

With more than 13 million people dying per year from infectious diseases Multidrug Resistance (MDR) in bacteria remains thegreatest challenge in public health care. This scenario, associated to the low turnover of new clinically approved antibioticdrugs makes the development of innovative therapeutic approaches to fight antibiotic resistance desperately needed toaddress this devastating societal problem. In this frame, SUPREME aims at the implementation of a novel strategy basedon unprecedented supramolecular platforms based on new cyclodextrin polymers integrating light-activatable nitric oxide (NO)photodonors (NOPD), alone and in combination with antibiotics currently employed in the clinic. The final goal is to exploitthe double role of NO generated with superb spatiotemporal control thanks to the light triggering, as: i)bactericidal species not suffering MDR when produced at high doses (micro molar); ii) inhibitor of the efflux pumps mainly responsiblefor MDR, when produced at low doses, to revert antibiotic resistance. Highly biocompatible branched polymers containing mixed (alpha, beta and gamma) cyclodextrin units will be used as suitable hosts able to self-assemble into nanoparticles or gelsencapsulating the therapeutic cargo with high efficiency. We will focus on NOPDs activatable exclusively with thebiocompatible visible light and on antibiotics representative of the classes of fluoroquinolones andtetracyclines, known to display resistance and severe side effects. Full chemico-physical and photochemical characterizationof the systems is planned as well as assessment of their efficacy against planktonic microbial cells and biofilms. The complementaryexpertise of the researcher and the supervisor supported by the private and academic teams hosting the fellow duringsecondments will create a multidisciplinary environment where all participants will benefit from reciprocal transfer ofknowledge.