ANR SPOTIACT - Dual stimuli-responsive infection-targeted pyrrolyldipyrrIn for photodynamic inactivation (DRIP-DIP)

Resume:

The spread of microbial infections represents a menace to the humanity and its development. However, the increase of multidrug resistance limits the efficacy of many common antibiotics and antifungals. Photodynamic therapy (PDT) is a photochemistry-based medical treatment using the light at a specific wavelength, a photosensitizer (PS) and molecular oxygen. The absorption of the light by the PS produces the reactive oxygen species (ROS), including singlet oxygen, both causing cell death followed by an inflammatory and immune response. Nowadays, PDI is a promising strategy to fight this thread because the ROS could damage various bacterial cell structures reducing the development of resistance. SPOTIACT proposes the synthesis, the photophysical analysis and the in vitro evaluation of novel pyrrolyldipyrrin-based PS, which will be designed to be dual stimuli-responsive and directed selectively to a wide range of microbes. To accomplish the project a stepwise approach will be used, and SPOTIACT will be divided in three work packages (WPs). First, molecular engineering of the proposed PS scaffold will be performed to draw a clear structure-activity relationship for an optimized PDI activity. Secondly, the most promising PS from WP1 will be modified to be activated by the glutathione and, subsequently, by the acidic pH, both featuring the microbial extracellular environment. Last, a directing moiety responsible for the selective interaction with the microbial surface will be introduced therefore avoiding interferences with mammalian cells. To validate each WP, the synthetic work will be completed by photophysical and theoretical studies as well as biological tests.