Development of an ex vivo lymph node explant model for identification of novel molecules active against leishmania major

Alex-Giovanny Peniche-Trujillo, Osorio Yaneth, Adam R. Renslo, Doug E. Frantz, Peter Melby, Bruno Travi

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Leishmaniasis is a vector-borne zoonotic infection affecting people in tropical and subtropical regions of the world. Current treatments for cutaneous leishmaniasis are difficult to administer, toxic, expensive, and limited in effectiveness and availability. Here we describe the development and application of a medium-throughput screening approach to identify new drug candidates for cutaneous leishmaniasis using an ex vivo lymph node explant culture (ELEC) derived from the draining lymph nodes of Leishmania major-infected mice. The ELEC supported intracellular amastigote proliferation and contained lymph node cell populations (and their secreted products) that enabled the testing of compounds within a system that mimicked the immunopathological environment of the infected host, which is known to profoundly influence parasite replication, killing, and drug efficacy. The activity of known antileishmanial drugs in the ELEC system was similar to the activity measured in peritoneal macrophages infected in vitro with L. major. Using the ELEC system, we screened a collection of 334 compounds, some of which we had demonstrated previously to be active against L. donovani, and identified 119 hits, 85% of which were confirmed to be active by determination of the 50% effective concentration (EC50). We found 24 compounds (7%) that had an in vitro therapeutic index (IVTI; 50% cytotoxic/effective concentration [CC50]/EC50)>100; 19 of the compounds had an EC50 below 1 μM. According to PubChem searchs, 17 of those compounds had not previously been reported to be active against Leishmania. We expect that this novel method will help to accelerate discovery of new drug candidates for treatment of cutaneous leishmaniasis.

Original languageEnglish (US)
Pages (from-to)78-87
Number of pages10
JournalAntimicrobial Agents and Chemotherapy
Volume58
Issue number1
DOIs
StatePublished - Jan 2014

Fingerprint

Leishmania major
Lymph Nodes
Cutaneous Leishmaniasis
Pharmaceutical Preparations
Leishmaniasis
Poisons
Leishmania
Zoonoses
Peritoneal Macrophages
Drug Discovery
Parasites
Population

ASJC Scopus subject areas

  • Pharmacology (medical)
  • Pharmacology
  • Infectious Diseases

Cite this

Development of an ex vivo lymph node explant model for identification of novel molecules active against leishmania major. / Peniche-Trujillo, Alex-Giovanny; Yaneth, Osorio; Renslo, Adam R.; Frantz, Doug E.; Melby, Peter; Travi, Bruno.

In: Antimicrobial Agents and Chemotherapy, Vol. 58, No. 1, 01.2014, p. 78-87.

Research output: Contribution to journalArticle

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