Analogs of Marinopyrrole A Show Enhancement to Observed In Vitro Potency against Acute Toxoplasma gondii Infection

Matthew C. Martens, Yan Liu, Austin G. Sanford, Alexander I. Wallick, Rosalie C. Warner, Rongshi Li, Paul H. Davis

Research output: Contribution to journalArticlepeer-review

Abstract

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 (IC50) of 0.31 mM, 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 IC50 values ranging from 0.09 to 0.17 mM (3.6- to 6.8-fold increase relative to pyrimethamine). No detectable cytotoxicity was observed up to 50 mM in human foreskin fibroblasts, with cytotoxicity in HepG2 cells ranging from ;28 to 50 mM, 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 mM. Taken together, these data support further development of marinopyrrole A analogs as promising anti- Toxoplasma molecules to further combat this prevalent infection.

Original languageEnglish (US)
Article numbere00794-21
JournalAntimicrobial Agents and Chemotherapy
Volume66
Issue number1
DOIs
StatePublished - Jan 2022
Externally publishedYes

Keywords

  • Analog
  • Antiparasitic agents
  • Marinopyrrole
  • Toxoplasma gondii

ASJC Scopus subject areas

  • Pharmacology
  • Pharmacology (medical)
  • Infectious Diseases

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