osu-03012 and Leishmaniasis--Visceral

Visceral leishmaniasis (VL) is associated with treatment complications due to the continued growth of resistant parasites toward currently available pathogen-directed therapeutics. To limit the emergence and combat resistant parasites there is a need to develop new anti-leishmanial drugs and alternative treatment approaches, such as host-directed therapeutics (HDTs). Discovery of new anti-leishmanial drugs including HDTs requires suitable in vitro assay systems. Herein, we modified and evaluated a series of resazurin assays against different life-stages of the VL causing parasite, Leishmania donovani to identify novel HDTs. We further analyzed the synergy of combinatorial interactions between traditionally used pathogen-directed drugs and HDTs for clearance of intracellular L. donovani. The inhibitory concentration at 50% (IC

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Drug Synergism; Drug Therapy, Combination; Host-Parasite Interactions; Humans; Leishmania donovani; Leishmaniasis, Visceral; Life Cycle Stages; Mice; Mice, Inbred BALB C; Phosphorylcholine; Pyrazoles; Sulfonamides

Leishmaniasis is a disease caused by parasites of Leishmania sp., which effects nearly 12 million people worldwide and is associated with treatment complications due to widespread parasite resistance toward pathogen-directed therapeutics. The current treatments for visceral leishmaniasis (VL), the systemic form of the disease, involve pathogen-mediated drugs and have long treatment regimens, increasing the risk of forming resistant strains. One way to limit emergence of resistant pathogens is through the use of host-mediated therapeutics. The host-mediated therapeutic AR-12, which is FDA IND-approved for cancer treatment, has shown activity against a broad spectrum of intracellular pathogens; however, due to hydrophobicity and toxicity, it is difficult to reach therapeutic doses. We have formulated AR-12 into microparticles (AR-12/MPs) using the novel biodegradable polymer acetalated dextran (Ace-DEX) and used this formulation for the systemic treatment of VL. Treatment with AR-12/MPs significantly reduced liver, spleen, and bone marrow parasite loads in infected mice, while combinatorial therapies with amphotericin B had an even more significant effect. Overall, AR-12/MPs offer a unique, host-mediated therapy that could significantly reduce the emergence of drug resistance in the treatment of VL.

Topics: Amphotericin B; Animals; Antiprotozoal Agents; Bone Marrow; Dextrans; Female; Hydrophobic and Hydrophilic Interactions; Leishmania donovani; Leishmaniasis, Visceral; Liver; Mesocricetus; Mice; Mice, Inbred BALB C; Microspheres; Polymers; Pyrazoles; Spleen; Sulfonamides