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Molecular Design and Synthesis Center

Antibacterial photosensitization through activation of coproporphyrinogen oxidase

AUTHORS

Surdel Matthew C , Horvath Dennis J , Lojek Lisa J , Fullen Audra R , Simpson Jocelyn , Dutter Brendan F , Salleng Kenneth J , Ford Jeremy B , Jenkins J Logan , Nagarajan Raju , Teixeira Pedro L , Albertolle Matthew , Georgiev Ivelin S , Jansen E Duco , Sulikowski Gary A , Lacy D Borden , Dailey Harry A , Skaar Eric P , . Proceedings of the National Academy of Sciences of the United States of America. 2017 12 8; 114(32). E6652-E6659

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.

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