Photosensitization of Bacterial Pathogens through Small Molecule Activators of Heme Biosynthesis
Technical Report,01 Dec 2017,30 Nov 2018
Vanderbilt University Medical Center Nashville United States
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Gram-positive bacteria cause the majority of skin and soft tissue infections SSTIs, resulting in the most common reason for clinic visits in the United States. Recently, it was discovered that Gram-positive pathogens utilize a unique heme biosynthesis pathway, which implicates this pathway as a novel target for development of antibacterial therapies. We report here the identification of a small molecule activator of coproporphyrinogen oxidase HemY from Gram-positive bacteria, an enzyme essential for heme biosynthesis. Activation of HemY induces accumulation of coproporphyrin III and leads to photosensitization of Gram-positive pathogens. In combination with light, small molecule HemY activators reduce bacterial burden and tissue ulceration in murine models of SSTI. Thus, small molecule activation of HemY represents an effective strategy for the development of light-based antimicrobial therapies. In addition, we have conjugated photactivators to mAbsthat target the surface of S. aureus increasing the antibacterial activity of light against S. aureus. Future work will focus on optimizing the combined activity of these small molecule and mAb photosensitizers.
- Medicine and Medical Research