Promising new antifungal treatment targeting chorismate synthase from Paracoccidioides brasiliensis [Chemistry; Biosynthesis]

Paracoccidioidomycosis (PCM), caused by the Paracoccidioides species, is a systemic mycosis with granulomatous character and a restricted therapeutic arsenal. The aim of this work was to search for new alternatives to treat largely neglected tropical mycosis, such as PCM. In this context, the enzymes of the shikimate pathway constitute excellent drug targets for conferring selective toxicity because this pathway is absent in humans but essential for the fungus. In this work, we have used a homology model of the chorismate synthase (EC 4.2.3.5) from Paracoccidioides brasiliensis (PbCS) and performed a combination of virtual screening and molecular dynamics to identify new potential inhibitors. The best hit, CP1, successfully adhered to pharmacologic criteria (adsorption-destribution-metabolism-excretion-toxicity) and was, therefore, used in in vitro experiments. Here, we demonstrate that CP1 binds with a dissociation constant of 64±1 μM to recombinant chorismate synthase from P. brasiliensis and inhibits enzymatic activity with an IC₅₀ value of 47±5 μM. As expected, CP1 showed no toxicity in three cell lines. On the other hand, CP1 reduced the fungal burden in lungs from treated mice, similar to itraconazole. In addition, the histopathological analysis showed that animals treated with CP1 displayed less lung tissue infiltration, fewer yeast cells, and large areas with preserved architecture. Therefore, CP1 was able to control PCM in mice with less inflammatory response and is, therefore, a promising candidate and lead structure for the development of drugs useful in PCM treatment.

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