Compositions and methods for drug sensitization of parasites

Abstract

Compositions and methods for inhibiting and/or sensitizing or re-sensitizing a parasite to an antiparasitic drug are provided. The compositions can comprise a rifamycin derivative or a pharmaceutically acceptable salt, hydrate, or prodrug thereof in an amount and formulation sufficient to inhibit or induce drug-sensitization in a parasite. The methods can comprise administering a rifamycin derivative or a pharmaceutically acceptable salt, hydrate, or prodrug thereof to a parasite in an amount and formulation sufficient to inhibit or induce drug-sensitization in the parasite.

1 . A composition comprising a pharmaceutical composition having the following formula: 
       
         
           
           
               
               
           
         
         wherein R comprises one of the following structures: 
       
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt, hydrate, or prodrug thereof in an amount and formulation sufficient to inhibit a P-glycoprotein pump in a parasite and thereby reduce the efflux of an antiparasitic drug from the parasite. 
     
     
         2 - 8 . (canceled) 
     
     
         9 . The composition of  claim 1 , further comprising a pharmaceutically acceptable carrier, a salt, a buffer, a preservative, or a solubility enhancer. 
     
     
         10 . The composition of  claim 1 , further comprising a macrocyclic lactone or quinoline antiparasitic drug. 
     
     
         11 . The composition of  claim 1 , further comprising one or more drugs. 
     
     
         12 . The composition of  claim 11 , wherein the one or more drugs includes one or more drugs selected from the group consisting of trimethoprim, pyrimethamine, proguanil, sulfamethoxazole, sulfadiazine, sulfadoxine, atovaquone, spiramycin, azithromycin, paromomycin, clindamycin, tetracycline, metronidazole, tinidazole, nitazoxanide, iodoquinol, chloroquine, primaquine, mefloquine, quinine, quinidine, praziquantel, oxaminquine, triclabendazole, niridazole, stibophen, trichlorfon, mebendazole, albendazole, niclosamide, ivermectin, doxycycline, diethylcarbamazine, pyrantel pamoate, permethrin, tiabendazole, levamisole, milbemycin, selamectin, doramectin, abamectin, mebendazole, fenbendazole, triclabendazole, flub endazole, diethylcarbazamine, suramin, levamisole, emodepside, monepantel, derquantel, rifoxanide, artemether, amodiaquine, artemisinin, moxidectin, hexylresorcinol, and combinations thereof. 
     
     
         13 - 21 . (canceled) 
     
     
         22 . The composition of  claim 1 , wherein the parasite is a species of the genus  Plasmodium , a species of the genus  Ascaris , a species of the genus  Enterobius , a species of the genus  Trichinella , a species of the genus  Haemonchus , a species of the genus  Aphelenchoides , a species of the genus  Ditylenchus , a species of the genus  Globodera , a species of the genus  Heterodera , a species of the genus  Longidorus , a species of the genus  Meloidogyne , a species of the genus  Nacobbus , a species of the genus  Pratylenchus , a species of the genus  Trichodorus , a species of the genus  Xiphinema , a species of the genus  Bursaphelenchus , a species of the genus  Fasciola , a species of the genus  Coccidoides , or a species of the genus  Onchocerca.    
     
     
         23 . The composition of  claim 1 , wherein the parasite is selected from the group consisting of  Pedicululs humanus, Phthiriasis pubis, Sarcoptes scabiei, Schistosoma mansoni, Schistosoma japonicum, Schistosoma haemotobium, Trichobilharzia regenti, Clonorchis simensis, Fasciola hepatica, Fasciola gigantica, Opisthorchis viverrinil, Paragonimus westermani, Paragonimus kellicotti, Fasciolopsis buski, Metagonimus yokagawai, Heterophyes heterophyes, Echinococcus granulosus, Echinococcus multilocularis, Taenia saginata, Taenia solium, Taenia asiatica, Hymenolpeis nana, Hymenolpeis diminuta, Diphyllobotrium latum, Diphyllobotrium mansonoides, Spirometra erinaceieuropaei, Dracunculus medinensis, Onchocerca volvulus, Loa boa, Mansonella perstans, Mansonella ozzardi, Mansonella streptocera, Wucheria bancrofti, Brugia malayi, Brugia timori, Gnathostoma spinigerum, Gnathostoma hispidium, Ancylostoma duodenale, Ancylostoma brazilienes, Necator americanus, Angiostrongylus cantonensis, Ascaris lumbricoides, Toxocara canis, Toxocara cati, Strongyloides stercoralis, Enterobius vermicularis, Trichinella spiralis, Trichuris trichiura, Cryptosporidium hominis, Cryptosporidium parvum, Isosporiasis belli, Cyclospora cayetanesis, Toxoplasma gondii, Balantidium coli, Entamoeba histolytica, dispar, Giardia lamblia, Trichmonas vaginalis, Dientamoeba fragilis, Blastocystis hominis, Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariea, Babesia divergens, Babesia microfti, Trypanosoma brucei, Trypanosoma cruzi, Leishomania mexicana, Leishomania aethiopica, Leishomania tropic, Leishomania braziliensis, Leishomania donovani , and  Leishomania infantum.    
     
     
         24 - 41 . (canceled) 
     
     
         42 . The composition of  claim 1 , wherein the pharmaceutical composition composition is 4-deoxy-3,4 [2-spiro-[1-(t-butyloxycarbonyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S, 4-deoxy-3,4[2-spiro-[1-(ethyloxycarbonyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S, 4-deoxy-3,4 [2-spiro-[1-(n-propyloxycarbonyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S, 4-deoxy-3,4[2-spiro-[1-(isobutyloxycarbonyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S, 4-deoxy-3,4[2-spiro-[1-(benzyloxycarbonyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S, 4-deoxy-3,4[2-spiro-[1-(ethylaminocarbonyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S, 4-deoxy-3,4[2-spiro-[1-(isopropyloxycarbonyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S, 4-deoxy-3,4[2-spiro-[1-(phenylaminocarbonyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S, 4-deoxy-3,4[2-spiro-[1-(acetyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S, 4-deoxy-3,4[2-spiro-[1-(beRTIoyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S, 4-deoxy-3,4[2-spiro-[1-(3,3-dimethylbutanoyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S, 4-deoxy-3,4[2-spiro-[1-(isobutylaminocarbonyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S, 4-deoxy-3,4[2-spiro-[1-(isopropylaminocarbonyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S, 4-deoxy-3,4 [2-spiro-[1-((1-methylpropyl) aminocarbonyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S, or 4-deoxy-3,4 [2-spiro-[1-(t-butylaminocarbonyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S. 
     
     
         43 . The composition of  claim 1 , wherein the pharmaceutical composition is 4-deoxy-3,4 [2-spiro-[1-(isobutyloxycarbonyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S. 
     
     
         44 . The composition of  claim 1 , wherein the pharmaceutical composition is 11-deoxy-11-amino-4-deoxy-3,4 [2-spiro-[1-(isobutyloxycarbonyl)-piperidin-4-yl]]-(1H)-imidazo-(2,5-dihydro)rifamycin S. 
     
     
         45 . The composition of  claim 1 , wherein the parasite is  Haemonchus contortus.    
     
     
         46 . The composition of  claim 1 , further comprising ivermectin. 
     
     
         47 . The composition of  claim 1 , further comprising iodoquinol. 
     
     
         48 . The composition of  claim 1 , further comprising chloroquine, primaquine, mefloquine, quinine, or quinidine. 
     
     
         49 . The composition of  claim 1 , further comprising praziquantel, or oxyminquine. 
     
     
         50 . The composition of  claim 1 , wherein reducing the efflux of an antiparasitic drug comprises reducing the efflux of a macrocyclic lactone or quinoline antiparasitic drug. 
     
     
         51 . The composition of  claim 10 , wherein reducing the efflux of an antiparasitic drug comprises reducing the efflux of a macrocyclic lactone or quinoline antiparasitic drug.