The apicomplexan parasite
Toxoplasma gondii
is the causative agent of toxoplasmosis, a globally distributed infection with severe clinical consequences for immunocompromised individuals and developing fetuses. There are few available treatments, and these are associated with potentially severe adverse effects. Marinopyrrole A, a compound discovered in a marine
Streptomyces
species, has previously been found to exhibit potent antimicrobial activity, prompting our interest in exploring efficacy against
Toxoplasma gondii
. We found that marinopyrrole A was a highly potent anti-
Toxoplasma
molecule, with an
in vitro
50% maximal inhibitory concentration (IC
50
) of 0.31 μM corresponding to a higher potency than that of the current standard of care (pyrimethamine); however, addition of 20% serum led to abrogation of potency, and toxicity to human cell lines was observed. Yet, application of marinopyrrole A to an
in vivo
lethal acute infection model facilitated significantly enhanced survival at doses of 5, 10, and 20 mg/kg. We then tested a series of marinopyrrole A analogs—RL002, RL003, and RL125—demonstrating significantly increased potency
in vitro
, with IC
50
values ranging from 0.09-0.17 μM (3.6-6.8X increase relative to pyrimethamine). No detectable cytotoxicity was observed up to 50 μM in human foreskin fibroblasts, with cytotoxicity in HepG2 cells ranging from ∼28-50 μM, corresponding to >200X selectivity for parasites over host cells. All analogs additionally showed reduced sensitivity to serum. Further, RL003 potently inhibited
in vitro
-generated bradyzoites at 0.245 μM. Taken together, these data support further development of marinopyrrole A analogs as promising anti-
Toxoplasma
molecules to further combat this prevalent infection.
