Revisiting Old Ionophore Lasalocid as a Novel Inhibitor of Multiple Toxins

Abstract

The ionophore lasalocid is widely used as a veterinary drug against coccidiosis. We found recently that lasalocid protects cells from two unrelated bacterial toxins, the cytotoxic necrotizing factor-1 (CNF1) from Escherichia. coli and diphtheria toxin. We evaluated lasalocid’s capacity to protect cells against other toxins of medical interest comprising toxin B from Clostridium difficile, Shiga-like toxin 1 from enterohemorrhagic E. coli and exotoxin A from Pseudomonas aeruginosa. We further characterized the impact of lasalocid on the endolysosomal and the retrograde pathways and organelle integrity, especially the Golgi apparatus. We found that lasalocid protects cells from all toxins tested and impairs the drop of vesicular pH along the trafficking pathways that are required for toxin sorting and translocation to the cytoplasm. Lasalocid also has an impact on the cellular distribution of GOLPH4 and GOLPH2 Golgi markers. Other intracellular trafficking compartments positive for EEA1 and Rab9A display a modified cellular pattern. In conclusion, lasalocid protects cells from multiple deadly bacterial toxins by corrupting vesicular trafficking and Golgi stack homeostasis.

C910 chemical compound inhibits the traffiking of several bacterial AB toxins with cross-protection against influenza virus

“…We previously screened 1,120 off-patent drugs from the Prestwick Chemical Library for their ability to protect cells against CNF1-induced Rac1 depletion for drug repurposing ( Mahtal et al., 2018 , 2020 ). Nevertheless, the identified compounds did not allow further development in the clinic.…”

“…Nevertheless, the identified compounds did not allow further development in the clinic. Indeed, their antitoxin activities required concentrations above their safety range, and in some instances, they had effects on multiple cellular organelles ( Mahtal et al., 2018 , 2020 ). The extended spectrum of protection conferred by C910 here points to its valuable pharmacological properties as much as it displays protection against IAV H1N1 without detectable toxicity in animals.…”

A screening pipeline identifies a broad-spectrum inhibitor of bacterial AB toxins with cross protection against influenza A virus H1N1 and SARS-CoV-2

“…Nevertheless, the identified compounds did not allow further development in the clinic. Indeed, their antitoxin activities required concentrations higher than their safety range, and in some instances, they had effects on multiple cellular organelles (58,59).…”

Natural Polyether Ionophores and Their Pharmacological Profile

“…The monomeric unit of lasalocid thallium salt is stabilized by strong, intramolecular aryl-Tl type-metal half sandwich bonding interactions. Homologs of lasalocid acid were also described [ 196 , 197 , 198 ].…”