title: Use of Optical Imaging Technology in the Validation of a New, Rapid, Cost-Effective Drug Screen as Part of a TieredIn VivoScreening Paradigm for Development of Drugs To Treat Cutaneous Leishmaniasis.
abstract: In any drug discovery and development effort, a reduction in the time of the lead optimization cycle is critical to decrease the time to license and reduce costs. In addition, ethical guidelines call for the more ethical use of animals to minimize the number of animals used and decrease their suffering. Therefore, any effort to develop drugs to treat cutaneous leishmaniasis requires multiple tiers ofin vivotesting that start with higher-throughput efficacy assessments and progress to lower-throughput models with the most clinical relevance. Here, we describe the validation of a high-throughput, first-tier, noninvasive model of lesion suppression that uses anin vivooptical imaging technology for the initial screening of compounds. A strong correlation between luciferase activity and the parasite load at up to 18 days postinfection was found. This correlation allows the direct assessment of the effects of drug treatment on parasite burden. We demonstrate that there is a strong correlation between drug efficacy measured on day 18 postinfection and the suppression of lesion size by day 60 postinfection, which allows us to reach an accurate conclusion on drug efficacy in only 18 days. Compounds demonstrating a significant reduction in the bioluminescence signal compared to that in control animals can be tested in lower-throughput, more definitive tests of lesion cure in BALB/c mice and Golden Syrian hamsters (GSH) using Old World and New World parasites.
authors.affiliation: Walter Reed Army Institute of Research, Experimental Therapeutics Branch of the Military Malaria Research Program, Silver Spring, Maryland, USA diana.caridha2.ctr@mail.mil mark_r_hickman@yahoo.com.
authors.forename: Diana
authors.initials: D
authors.lastname: Caridha
authors.affiliation: Walter Reed Army Institute of Research, Experimental Therapeutics Branch of the Military Malaria Research Program, Silver Spring, Maryland, USA.
authors.forename: Sandi
authors.initials: S
authors.lastname: Parriot
authors.affiliation: Walter Reed Army Institute of Research, Experimental Therapeutics Branch of the Military Malaria Research Program, Silver Spring, Maryland, USA.
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Hudson
authors.affiliation: Institut Pasteur, Unité d'Immunophysiologie et Parasitisme Intracellulaire, Département de Parasitologie et Mycologie, Paris, France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Lang
authors.affiliation: Walter Reed Army Institute of Research, Experimental Therapeutics Branch of the Military Malaria Research Program, Silver Spring, Maryland, USA.
authors.forename: Franklyn
authors.initials: F
authors.lastname: Ngundam
authors.affiliation: Walter Reed Army Institute of Research, Experimental Therapeutics Branch of the Military Malaria Research Program, Silver Spring, Maryland, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Leed
authors.affiliation: Walter Reed Army Institute of Research, Experimental Therapeutics Branch of the Military Malaria Research Program, Silver Spring, Maryland, USA.
authors.forename: Jenell
authors.initials: J
authors.lastname: Sena
authors.affiliation: Walter Reed Army Institute of Research, Experimental Therapeutics Branch of the Military Malaria Research Program, Silver Spring, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Harris
authors.affiliation: Walter Reed Army Institute of Research, Experimental Therapeutics Branch of the Military Malaria Research Program, Silver Spring, Maryland, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: O'Neil
authors.affiliation: Walter Reed Army Institute of Research, Experimental Therapeutics Branch of the Military Malaria Research Program, Silver Spring, Maryland, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Sciotti
authors.affiliation: Walter Reed Army Institute of Research, Experimental Therapeutics Branch of the Military Malaria Research Program, Silver Spring, Maryland, USA.
authors.forename: Lisa
authors.initials: L
authors.lastname: Read
authors.affiliation: Institut Pasteur, Unité d'Immunophysiologie et Parasitisme Intracellulaire, Département de Parasitologie et Mycologie, Paris, France.
authors.forename: Herve
authors.initials: H
authors.lastname: Lecoeur
authors.affiliation: Walter Reed Army Institute of Research, Experimental Therapeutics Branch of the Military Malaria Research Program, Silver Spring, Maryland, USA diana.caridha2.ctr@mail.mil mark_r_hickman@yahoo.com.
authors.forename: Mark
authors.initials: M
authors.lastname: Hickman
authors.affiliation: Walter Reed Army Institute of Research, Experimental Therapeutics Branch of the Military Malaria Research Program, Silver Spring, Maryland, USA.
authors.forename: Max
authors.initials: M
authors.lastname: Grogl
mesh_terms: D000666:Amphotericin B / Q000494:pharmacology; D000818:Animals; D000981:Antiprotozoal Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical / Q000191:economics / Q000379:methods; D005260:Female; D049454:Firefly Luciferin / Q000008:administration & dosage; D015725:Fluconazole / Q000494:pharmacology; D017930:Genes, Reporter; D057166:High-Throughput Screening Assays; D018320:Leishmania major / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D016773:Leishmaniasis, Cutaneous / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008163:Luminescent Measurements; D008264:Macrophages / Q000166:cytology / Q000187:drug effects; D008536:Meglumine / Q000494:pharmacology; D000077485:Meglumine Antimoniate; D008647:Mesocricetus; D051379:Mice; D008807:Mice, Inbred BALB C; D015242:Ofloxacin / Q000494:pharmacology; D061848:Optical Imaging; D030781:Organisms, Genetically Modified; D009942:Organometallic Compounds / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology
chemical_list: D000981:Antiprotozoal Agents; D009942:Organometallic Compounds; D014230:Triazoles; C068538:liposomal amphotericin B; D049454:Firefly Luciferin; D008536:Meglumine; C101425:posaconazole; D000077485:Meglumine Antimoniate; D000666:Amphotericin B; D015725:Fluconazole; D015242:Ofloxacin; D008156:Luciferases
keywords: BALB/c mouse; Golden Syrian hamster; Leishmania lesion cure; Leishmania lesion suppression; antileishmanial drugs; bioluminescence signal; cutaneous leishmaniasis; in vivo drug screen; in vivo imaging system; mouse models; transgenic Leishmania major