This proposal describes a breakthrough development involving the chemical design and synthesis of stabilized bacteriochlorin molecules to carry out photodynamic therapy. These novel photosensitizers (PS) have very intense absorption bands in the near-infrared region of the spectrum where tissue penetration is maximized and good yields of the triplet excited state that produces the reactive oxygen species. The first chosen application of these novel and highly promising PS is to preferentially kill infectious microorganisms and treat localized infections. Most PS that are under investigation for the photodynamic therapy (PDT) of cancer and other diseases are based on the tetrapyrrole nucleus, owing to their ability to be accumulated by malignant cells or tumors. A chief limitation of existing PS has been the lack of suitable near-IR absorption since light in the deep-red/near-IR offers the deepest tissue penetration. Bacteriochlorins (tetrapyrroles containing two pyrrole rings that are reduced at the??- pyrrole-positions) would be ideal PS due to their strong NIR absorption, but until now have suffered from extreme instability (due to spontaneous dehydrogenation to yield oxidized products) and a lack of synthetic tunability. A recent revolution in molecular design and chemical synthesis has opened the door to stable, versatile bacteriochlorins with strong absorptions in the NIR. The combination of non-toxic dyes and harmless light known as antimicrobial PDT can efficiently kill pathogens (including multi-antibiotic resistance amongst pathogenic microbes) and can be usefully employed to fight infections provided the PS shows selectivity for bacteria over host tissue. It is thought that polycationic PS molecules not only are optimal for binding and penetration of multiple classes of microorganism, but also show temporal selectivity for microbes over mammalian cells provided the PS is directly introduced into the infected area. In this proposal, seven types of cationic bacteriochlorins will be designed, synthesized, and tested for PDT activity against a broad spectrum of pathogenic microorganisms in vitro. The two best performing bacteriochlorins will then be tested in a mouse model of a potentially lethal wound infection and monitored by bioluminescence imaging. ? ? ?
