Photosensitization of Bacterial Pathogens through Small Molecule Activators of Heme Biosynthesis
Abstract
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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Dec 01, 2018
- Accession Number
- AD1095591
Entities
People
- Duco Jansen
- Eric P. Skaar
- Gary Sulikowski
Organizations
- Vanderbilt University Medical Center