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Sulikowski Lab

Antibacterial photosensitization through activation of coproporphyrinogen oxidase.

AUTHORS

Surdel MCMatthew C , Horvath DJ Dennis J , Lojek LJ Lisa J , Fullen AR Audra R , Simpson J Jocelyn , Dutter BF Brendan F , Salleng KJ Kenneth J , Ford JB Jeremy B , Jenkins JL J Logan , Nagarajan R Raju , Teixeira PL Pedro L , Albertolle M Matthew , Georgiev IS Ivelin S , Jansen ED E Duco , Sulikowski GA Gary A , Lacy DB D Borden , Dailey HA Harry A , Skaar EP Eric P . Proceedings of the National Academy of Sciences of the United States of America. 2017 8 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.

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.