Disease Information

General Information of the Disease (ID: DIS00176)

• Name: Leishmaniasis
• ICD: ICD-11: 1F54

Type(s) of Resistant Mechanism of This Disease

  IDUE: Irregularity in Drug Uptake and Drug Efflux

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 2 drug(s) in total

Allopurinol

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: S-adenosylmethionine synthase (METK) [1]

• Resistant Disease: Visceral leishmaniasis [ICD-11: 1F54.0]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Allopurinol
• Experimental Note: Discovered Using In-vivo Testing Model
• In Vitro Model: Leishmania infantum strain; 5671
• Experiment for Molecule Alteration: Quantitative PCR assays
• Mechanism Description: A reduction in copy number for LinJ.30.3560, encoding the S-adenosylmethionine synthetase (METK) gene, was found in two resistant clinical isolates and four induced resistant clonal strains. Using quantitative real time PCR, this reduction in METK copy number was also found in three additional resistant clinical isolates. Since allopurinol can be incorporated into energetic nucleotides such as ATP it may be that such allopurinol containing nucleotides inhibit S-adenosylmethionine synthetase or are utilized by it, producing faulty products, which in turn inhibit the parasite's growth. Down-regulation of S-adenosylmethionine synthetase in resistant strains may reduce the levels of such faulty products.

Miltefosine

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 3 (ABCB4) [2]

• Resistant Disease: Leishmaniasis [ICD-11: 1F54.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Miltefosine
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: In addition, the overexpression of ABC transporters ABCB4(MDR1), ABCG4, and ABCG6 has also been described to be associated with an increased resistance to several alkyl-lysophospholipids analogues, including MIL in Leishmania, due to a reduced intracellular accumulation because of increased efflux of the drug across the plasma membrane.

Key Molecule: ATP binding cassette subfamily G member 4 (ABCG4) [2]

• Resistant Disease: Leishmaniasis [ICD-11: 1F54.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Miltefosine
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: In addition, the overexpression of ABC transporters ABCB4(MDR1), ABCG4, and ABCG6 has also been described to be associated with an increased resistance to several alkyl-lysophospholipids analogues, including MIL in Leishmania, due to a reduced intracellular accumulation because of increased efflux of the drug across the plasma membrane.

Key Molecule: ABC transporter G family member 6 (ABCG6) [2]

• Resistant Disease: Leishmaniasis [ICD-11: 1F54.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Miltefosine
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: In addition, the overexpression of ABC transporters ABCB4(MDR1), ABCG4, and ABCG6 has also been described to be associated with an increased resistance to several alkyl-lysophospholipids analogues, including MIL in Leishmania, due to a reduced intracellular accumulation because of increased efflux of the drug across the plasma membrane.

Key Molecule: Multidrug resistance protein 1 (ABCB1) [2]

• Resistant Disease: Leishmaniasis [ICD-11: 1F54.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Miltefosine
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: In addition, the overexpression of ABC transporters ABCB4(MDR1), ABCG4, and ABCG6 has also been described to be associated with an increased resistance to several alkyl-lysophospholipids analogues, including MIL in Leishmania, due to a reduced intracellular accumulation because of increased efflux of the drug across the plasma membrane.

Key Molecule: Leishmania miltefosine transporter (LMT) [2]

• Resistant Disease: Leishmaniasis [ICD-11: 1F54.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Miltefosine
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: The uptake of MIL and other alkyl-glycerophospholipids in Leishmania requires a translocation machinery that includes a P-type ATPase named the Leishmania miltefosine transporter (LMT), which is responsible for the translocation of phospholipids from the exoplasmic to the cytoplasmic leaflet of the plasma membrane of Leishmania. The function of LMT depends on its binding to a specific B subunit of LMT called LRos3, which belongs to the CDC50/LEM3 protein family. Both proteins are mutually dependent for their function and their localization at the plasma membrane of Leishmania, being required for MIL uptake and susceptibility.

Key Molecule: Miltefosine transporter beta subunit (ROS3) [2]

• Resistant Disease: Leishmaniasis [ICD-11: 1F54.1]
• Molecule Alteration: Expression; Down-regulation
• Resistant Drug: Miltefosine
• Experimental Note: Discovered Using In-vivo Testing Model
• Mechanism Description: The uptake of MIL and other alkyl-glycerophospholipids in Leishmania requires a translocation machinery that includes a P-type ATPase named the Leishmania miltefosine transporter (LMT), which is responsible for the translocation of phospholipids from the exoplasmic to the cytoplasmic leaflet of the plasma membrane of Leishmania. The function of LMT depends on its binding to a specific B subunit of LMT called LRos3, which belongs to the CDC50/LEM3 protein family. Both proteins are mutually dependent for their function and their localization at the plasma membrane of Leishmania, being required for MIL uptake and susceptibility.

References

• Ref 1: Resistance of Leishmania infantum to allopurinol is associated with chromosome and gene copy number variations including decrease in the S-adenosylmethionine synthetase (METK) gene copy number .Int J Parasitol Drugs Drug Resist. 2018 Dec;8(3):403-410. doi: 10.1016/j.ijpddr.2018.08.002. Epub 2018 Aug 23. 10.1016/j.ijpddr.2018.08.002
• Ref 2: Drug resistance and treatment failure in leishmaniasis: A 21st century challenge .PLoS Negl Trop Dis. 2017 Dec 14;11(12):e0006052. doi: 10.1371/journal.pntd.0006052. eCollection 2017 Dec. 10.1371/journal.pntd.0006052