TY - JOUR
T1 - Analogs of Marinopyrrole A Show Enhancement to Observed In Vitro Potency against Acute Toxoplasma gondii Infection
AU - Martens, Matthew C.
AU - Liu, Yan
AU - Sanford, Austin G.
AU - Wallick, Alexander I.
AU - Warner, Rosalie C.
AU - Li, Rongshi
AU - Davis, Paul H.
N1 - Funding Information:
This work was supported by NIH grant P20GM103427. Further support was received from the University of Nebraska at Omaha FUSE program and the Nebraska Research Initiative. This work was also completed utilizing the Holland Computing Center of the University of Nebraska, which also receives support from the Nebraska Research Initiative. This publication’s contents are the sole responsibility of the authors and do not necessarily represent the official views of the funding agencies. We declare no competing interests.
Publisher Copyright:
© 2022 American Society for Microbiology.
PY - 2022/1
Y1 - 2022/1
N2 - 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.
AB - 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.
KW - Analog
KW - Antiparasitic agents
KW - Marinopyrrole
KW - Toxoplasma gondii
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U2 - 10.1128/AAC.00794-21
DO - 10.1128/AAC.00794-21
M3 - Article
C2 - 34662196
AN - SCOPUS:85123117964
VL - 66
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 1
M1 - e00794-21
ER -