Snapshot Profiling of the Antileishmanial Potency of Lead Compounds and Drug Candidates against Intracellular Leishmania donovani Amastigotes, with a Focus on Human-Derived Host Cells

Antimicrob Agents Chemother. 2017 Feb 23;61(3):e01228-16. doi: 10.1128/AAC.01228-16. Print 2017 Mar.

Abstract

This study characterized the in vitro potencies of antileishmanial agents against intracellular Leishmania donovani amastigotes in primary human macrophages, obtained with or without CD14-positive monocyte enrichment, phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells, and mouse peritoneal exudate macrophages (PEMs). Host cell-dependent potency was confirmed for pentavalent and trivalent antimony. Fexinidazole was inactive against intracellular amastigotes across the host cell panel. Fexinidazole sulfone, (R)-PA-824, (S)-PA-824, and VL-2098 displayed similar potency in all of the host cells tested.

Keywords: Leishmania donovani; drug potency; host cell.

MeSH terms

  • Animals
  • Antimony / pharmacology*
  • Antiprotozoal Agents / pharmacology*
  • Cell Differentiation / drug effects
  • Cell Line
  • Host-Pathogen Interactions / drug effects*
  • Humans
  • Inhibitory Concentration 50
  • Leishmania donovani / drug effects*
  • Leishmania donovani / growth & development
  • Leishmania donovani / metabolism
  • Macrophages / drug effects*
  • Macrophages / parasitology
  • Mice
  • Mice, Knockout
  • Monocytes / drug effects
  • Monocytes / parasitology
  • Nitroimidazoles / pharmacology*
  • Primary Cell Culture
  • Stereoisomerism
  • Tetradecanoylphorbol Acetate / pharmacology

Substances

  • Antiprotozoal Agents
  • Nitroimidazoles
  • pretomanid
  • fexinidazole
  • Antimony
  • Tetradecanoylphorbol Acetate