Use of Optical Imaging Technology in the Validation of a New, Rapid, Cost-Effective Drug Screen as Part of a Tiered In Vivo Screening Paradigm for Development of Drugs To Treat Cutaneous Leishmaniasis

被引：0

作者：

Caridha, Diana ^{[1
]}

Parriot, Sandi ^{[1
]}

Hudson, Thomas H. ^{[1
]}

Lang, Thierry ^{[2
]}

Ngundam, Franklyn ^{[1
]}

Leed, Susan ^{[1
]}

Sena, Jenell ^{[1
]}

Harris, Michael ^{[1
]}

O'Neil, Michael ^{[1
,3
]}

Sciotti, Richard ^{[1
]}

Read, Lisa ^{[1
]}

Lecoeur, Herve ^{[2
]}

Hickman, Mark ^{[1
]}

Grogl, Max ^{[1
,4
]}

机构：

[1] Walter Reed Army Inst Res, Expt Therapeut Branch, Mil Malaria Res Program, Silver Spring, MD 20910 USA

[2] Inst Pasteur, Unite Immunophysiol & Parasitisme Intracellulaire, Dept Parasitol & Mycol, Paris, France

[3] NIAID, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

[4] US Naval Med Res Unit 6, Washington, DC USA

来源：

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY | 2017年 / 61卷 / 04期

关键词：

cutaneous leishmaniasis; Golden Syrian hamster; BALB/c mouse; in vivo imaging system; Leishmania lesion cure; Leishmania lesion suppression; antileishmanial drugs; bioluminescence signal; in vivo drug screen; mouse models; transgenic Leishmania major; FLUORESCENT PROTEIN; VIANNIA BRAZILIENSIS; VISCERAL LEISHMANIASIS; MESOCRICETUS-AURATUS; EXPERIMENTAL-MODELS; CELL-DEVELOPMENT; INFECTION; VITRO; MILTEFOSINE; FLUCONAZOLE;

D O I：

10.1128/AAC.02048-16

中图分类号：

Q93 [微生物学];

学科分类号：

071005 ; 100705 ;

摘要：

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 of in vivo testing 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 an in vivo optical 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.

引用

页数：15