Antibacterial photosensitization through activation of coproporphyrinogen oxidase.

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.

Optimization of optical parameters for improved photodynamic therapy of Staphylococcus aureus using endogenous coproporphyrin III.

BACKGROUND: It has recently been shown that endogenous photosensitization of Gram-positive bacteria is achieved through the accumulation of the heme precursor coproporphyrin III and not protoporphyrin IX, as was previously assumed. As previous studies have operated under this assumption, the efficacy of optimal targeting of the absorption peaks of coproporphyrin III has not been explored. METHODS: Staphylococcus aureus was endogenously photosensitized through the addition of either the small molecule VU0038882, aminolevulinic acid, or both. The efficacy of five different LEDs whose wavelengths target different coproporphyrin III absorption peaks were determined in vitro. Based on these in vitro measurements, the effectiveness of utilizing these LEDs to treat a skin infection was predicted using a Monte Carlo simulation to estimate the fluence rates and resulting bacterial reductions as a function of depth. RESULTS: Optimal targeting of the Soret band provided a 4.7-log improvement as compared to previously utilized wavelengths. Activation of the Q-bands was found to provide similar cytotoxic effects but required significantly larger doses of light. Despite near sterilization in vitro, it was predicted that Soret band targeted light would only provide at least a 2 log-reduction up to 430 µm into the skin while Q-band targeted light could remain effective up to 1 mm in depth. Multiplexing these different wavelengths was found to provide a further 0.5-1.0 log-reduction in bacterial viability. CONCLUSIONS: Accurate targeting of coproporphyrin III has shown that endogenous photodynamic therapy has the potential to be further developed into an effective treatment of skin and soft tissue infections caused by Gram-positive bacteria.