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 the

greatest challenge in public health care. This scenario, associated to the low turnover of new clinically approved antibiotic

drugs makes the development of innovative therapeutic approaches to fight antibiotic resistance desperately needed to

address this devastating societal problem. In this frame, SUPREME aims at the implementation of a novel strategy based

on 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 exploit

the 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 responsible

for 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 gels

encapsulating the therapeutic cargo with high efficiency. We will focus on NOPDs activatable exclusively with the

biocompatible visible light and on antibiotics representative of the classes of fluoroquinolones and

tetracyclines, known to display resistance and severe side effects. Full chemico-physical and photochemical characterization

of the systems is planned as well as assessment of their efficacy against planktonic microbial cells and biofilms. The complementary

expertise of the researcher and the supervisor supported by the private and academic teams hosting the fellow during

secondments will create a multidisciplinary environment where all participants will benefit from reciprocal transfer of

knowledge.