Analogs of Marinopyrrole A Show Enhancement to Observed In Vitro Potency against Acute Toxoplasma gondii Infection
| Autor: | Paul H. Davis, Yan Liu, Matthew C Martens, Rongshi Li, Rosalie C Warner, Alexander I Wallick, Austin G. Sanford |
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| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Pharmacology
biology Chemistry Antiprotozoal Agents Toxoplasma gondii biology.organism_classification In vitro Infectious Diseases Pyrimethamine In vivo Toxicity medicine Potency Humans Pharmacology (medical) Experimental Therapeutics Pyrroles Cytotoxicity IC50 Toxoplasma Toxoplasmosis medicine.drug |
| Zdroj: | Antimicrob Agents Chemother |
| Popis: | 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) and demonstrated significantly increased potency in vitro, with IC(50) values ranging from 0.09 to 0.17 μM (3.6- to 6.8-fold 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 to 50 μM, corresponding to >200-fold 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. |
| Databáze: | OpenAIRE |
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