Leishmania panamensis infection and antimonial drugs modulate expression of macrophage drug transporters and metabolizing enzymes: impact on intracellular parasite survival.

Abstract

OBJECTIVES:

Treatment failure is multifactorial. Despite the importance of host cell drug transporters and metabolizing enzymes in the accumulation, distribution and metabolism of drugs targeting intracellular pathogens, their impact on the efficacy of antileishmanials is unknown. We examined the contribution of pharmacologically relevant determinants in human macrophages in the antimony-mediated killing of intracellular Leishmania panamensis and its relationship with the outcome of treatment with meglumine antimoniate.

METHODS:

Patients with cutaneous leishmaniasis who failed (n = 8) or responded (n =8) to treatment were recruited. Gene expression profiling of pharmacological determinants in primary macrophages was evaluated by quantitative RT-PCR and correlated to the drug-mediated intracellular parasite killing. Functional validation was conducted through short hairpin RNA gene knockdown.

RESULTS:

Survival of L. panamensis after exposure to antimonials was significantly higher in macrophages from patients who failed treatment. Sixteen macrophage drug-response genes were modulated by infection and exposure to meglumine antimoniate. Correlation analyses of gene expression and intracellular parasite survival revealed the involvement of host cell metallothionein-2A and ABCB6 in the survival of Leishmania during exposure to antimonials. ABCB6 was functionally validated as a transporter of antimonial compounds localized in both the cell and phagolysosomal membranes of macrophages, revealing a novel mechanism of host cell-mediated regulation of intracellular drug exposure and parasite survival within phagocytes.

CONCLUSIONS:

These results provide insight into host cell mechanisms regulating the intracellular exposure of Leishmania to antimonials and variations among individuals that impact parasite survival. Understanding of host cell determinants of intracellular pharmacokinetics/pharmacodynamics opens new avenues to improved drug efficacy for intracellular pathogens.

• Authors: Maria Adelaida Gómez, Adriana Navas, Ricardo Márquez, Laura Jimena Rojas, Deninson Alejandro Vargas, Victor Manuel Blanco, Roni Koren, Dan Zilberstein, Nancy Gore Saravia
• Journal: The Journal of antimicrobial chemotherapy (J Antimicrob Chemother) Vol. 69 Issue 1 Pg. 139-49 (Jan 2014) ISSN: 1460-2091 [Electronic] England
• PMID: 23975742 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiprotozoal Agents
• Membrane Transport Proteins
• Organometallic Compounds
• Meglumine
• Meglumine Antimoniate

Topics

• Adult
• Antiprotozoal Agents (pharmacology, therapeutic use)
• Cell Survival
• Female
• Gene Expression Profiling
• Host-Pathogen Interactions
• Humans
• Leishmania (drug effects, immunology, physiology)
• Macrophages (drug effects, parasitology)
• Male
• Meglumine (pharmacology, therapeutic use)
• Meglumine Antimoniate
• Membrane Transport Proteins (biosynthesis, genetics)
• Middle Aged
• Organometallic Compounds (pharmacology, therapeutic use)
• Young Adult