2. Academic Validation
  3. Antibacterial photosensitization through activation of coproporphyrinogen oxidase

Antibacterial photosensitization through activation of coproporphyrinogen oxidase

  • Proc Natl Acad Sci U S A. 2017 Aug 8;114(32):E6652-E6659. doi: 10.1073/pnas.1700469114.
Matthew C Surdel 1,  Dennis J Horvath Jr 1,  Lisa J Lojek 1,  Audra R Fullen 1,  Jocelyn Simpson 1,  Brendan F Dutter 2 3,  Kenneth J Salleng 1,  Jeremy B Ford 4,  J Logan Jenkins 4,  Raju Nagarajan 5,  Pedro L Teixeira 6,  Matthew Albertolle 3 7,  Ivelin S Georgiev 1 5 8,  E Duco Jansen 4,  Gary A Sulikowski 2 3,  D Borden Lacy 1 4,  Harry A Dailey 9 10 11,  Eric P Skaar 12
Affiliations

Affiliations

  • 1 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.
  • 2 Department of Chemistry, Vanderbilt University, Nashville, TN 37232.
  • 3 Vanderbilt Institute for Chemical Biology, Nashville, TN 37232.
  • 4 Department of Biomedical Engineering, Vanderbilt University, Nashville, TN 37232.
  • 5 Vanderbilt Vaccine Center, Vanderbilt University Medical Center, Nashville, TN 37232.
  • 6 Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, TN 37203.
  • 7 Department of Biochemistry, Vanderbilt University, Nashville, TN 37232.
  • 8 Department of Electrical Engineering and Computer Science, Vanderbilt University, Nashville, TN 37232.
  • 9 Biomedical and Health Sciences Institute, University of Georgia, Athens, GA 30602.
  • 10 Department of Microbiology, University of Georgia, Athens, GA 30602.
  • 11 Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602.
  • 12 Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; eric.skaar@vanderbilt.edu.
PMID: 28739897 DOI: 10.1073/pnas.1700469114
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 use a unique heme biosynthesis pathway, which implicates this pathway as a target for development of Antibacterial therapies. We report here the identification of a small-molecule activator of coproporphyrinogen oxidase (CgoX) from Gram-positive bacteria, an Enzyme essential for heme biosynthesis. Activation of CgoX induces accumulation of coproporphyrin III and leads to photosensitization of Gram-positive pathogens. In combination with LIGHT, CgoX activation reduces Bacterial burden in murine models of SSTI. Thus, small-molecule activation of CgoX represents an effective strategy for the development of light-based antimicrobial therapies.

Keywords

CgoX; antibiotic; bacteria; heme; photosensitization.

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