Drug Information

Drug (ID: DG00661) and It's Reported Resistant Information

• Name: Miltefosine
• Synonyms: Miltefosine; 58066-85-6; Hexadecylphosphocholine; Miltex; Impavido; Hexadecylphosphorylcholine; HDPC; n-Hexadecylphosphorylcholine; Miltefosinum; Miltefosina; 1-Hexadecylphosphorylcholine; hexadecyl 2-(trimethylammonio)ethyl phosphate; hexadecyl phosphocholine; Miltefosin C; n-hexadecylphosphocholine; hexadecyl 2-(trimethylazaniumyl)ethyl phosphate; D-18506; miltefosin; C21H46NO4P; UNII-53EY29W7EC; NSC605583; hexadecyl (2-(trimethylAmmonio)ethyl) phosphate; monohexadecylphosphocholine; CHEMBL125; monohexadecylphosphorylcholine; HePC;Hexadecyl phosphocholine; 53EY29W7EC; CHEBI:75283; MFCD00133396; MMV688990; NSC-605583; NSC-758968; NCGC00095169-01; Miltefos; DSSTox_CID_25942; DSSTox_RID_81240; DSSTox_GSID_45942; Miltefosinum [INN-Latin]; Miltefosina [INN-Spanish]; Miltefosine [INN:BAN]; Fos-choline 16; Miltefosine (INN); CAS-58066-85-6; D 18506; Choline hexadecyl phosphate; BRN 3690495; Miltextrade mark; HePC Hydrate; Impavidotrade mark; D18506; Impavido (TN); Choline, inner salt; TF-002; 2-(((Hexadecyloxy)hydroxyphosphinyl)oxy)-N,N,N-trimethylethanaminium hydroxide, inner salt; NSC 605583; Choline hydroxide, hexadecyl hydrogen phosphate, inner salt; Choline phosphate, hexadecyl ester, hydroxide, inner salt (6CI); Hexadecyl Phosphorylcholine; H-1850; M-7200; Ethanaminium, 2-(((hexadecyloxy)hydroxyphosphinyl)oxy)-N,N,N-trimethyl-, hydroxide, inner salt; SCHEMBL26215; 4-04-00-01460 (Beilstein Handbook Reference); SPECTRUM1505329; DTXSID7045942; GTPL11355; Hexadecyl Phosphorylcholine Hydrate; HMS1922D16; HMS2089J15; HMS3649I09; Pharmakon1600-01505329; hexadecylphosphocholine, miltefosine; BCP04506; miltefosine (hexadecylphosphocholine); Tox21_111466; BDBM50034220; CCG-35584; CCG-36097; CCG-40025; DL-131; Hexadecyl 2-(trimethyl-.lambda.~5~-azanyl)ethyl hydrogen phosphate; NSC758968; s3056; 1-N-HEXADECYLPHOSPHORYLCHOLINE; AKOS015914886; Tox21_111466_1; BCP9000927; DB09031; NCGC00095169-02; NCGC00095169-03; NCGC00095169-05; NCGC00095169-07; HY-13685; BCP0726000071; FT-0608148; M2445; hexadecyloxy-2-trimethylammonioethylphosphorate; D02494; AB00642217-03; AB00642217_04; Miltefosine, >=98% (perchloric acid titration); A831718; Q411787; Hexadecyl 2-(Trimethylammonio)ethyl Phosphate Hydrate; 2-[hexadecoxy(hydroxy)phosphoryl]oxyethyl-trimethyl-ammonium; Phosphoric Acid Hexadecyl 2-(Trimethylammonio)ethyl Ester; [2-(Hexadecyloxy-hydroxy-phosphoryloxy)-ethyl]-trimethyl-ammonium; 3, 4-hydroxy-N,N,N-trimethyl-, hydroxide, inner salt, 4-oxide; hexadecyl 2-(trimethyl-lambda~5~-azanyl)ethyl hydrogen phosphate; Phosphoric Acid Hexadecyl 2-(Trimethylammonio)ethyl Ester Hydrate; 2-(((Hexadecyloxy)hydroxyphosphinyl)oxy)-N,N,N-trimethylethanaminium hydroxide
• Indication:
  In total 2 Indication(s)
  Leishmaniasis [ICD-11: 1F54]; Approved; [1]
  Visceral leishmaniasis [ICD-11: 1F54]; Approved; [1]
• Drug Resistance Disease(s):
  Disease(s) with Resistance Information Discovered by Cell Line Test for This Drug (1 diseases)
  Fungal infection [ICD-11: 1F29-1F2F]; [2]
  Disease(s) with Clinically Reported Resistance for This Drug (1 diseases)
  Leishmaniasis [ICD-11: 1F54]; [3]
  Disease(s) with Resistance Information Validated by in-vivo Model for This Drug (1 diseases)
  Leishmaniasis [ICD-11: 1F54]; [1]
• Target: Phospholipase A2 (PLA2G1B); PA21B_HUMAN; [1]
• Formula: C21H46NO4P
• IsoSMILES: CCCCCCCCCCCCCCCCOP(=O)([O-])OCC[N+](C)(C)C
• InChI: 1S/C21H46NO4P/c1-5-6-7-8-9-10-11-12-13-14-15-16-17-18-20-25-27(23,24)26-21-19-22(2,3)4/h5-21H2,1-4H3
• InChIKey: PQLXHQMOHUQAKB-UHFFFAOYSA-N
• PubChem CID: 3599
• ChEBI ID: CHEBI:75283
• TTD Drug ID: D00FGR
• INTEDE ID: DR1092
• DrugBank ID: DB09031

Type(s) of Resistant Mechanism of This Drug

  IDUE: Irregularity in Drug Uptake and Drug Efflux

Drug Resistance Data Categorized by Their Corresponding Diseases

ICD-01: Infectious/parasitic diseases

Fungal infection [ICD-11: 1F29-1F2F]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: RTA3 protein [2]

• Resistant Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SC5314 cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: Susceptibility testing
• Mechanism Description: Activating mutations in the ZCFs Mrr1, Tac1, and Upc2 frequently cause acquired resistance to the widely used antifungal drug fluconazole in the pathogenic yeast?Candida albicans. Similar to a hyperactive Tac1, a constitutively active form of the ZCF Znc1 causes increased fluconazole resistance by upregulating the multidrug efflux pump-encoding gene?CDR1. Hyperactive forms of both Tac1 and Znc1 also cause overexpression of?RTA3, which encodes a seven-transmembrane receptor protein involved in the regulation of asymmetric lipid distribution in the plasma membrane.?RTA3?expression is also upregulated by miltefosine, an antiparasitic drug that is active against fungal pathogens and considered for treatment of invasive candidiasis, and?rta3delta mutants are hypersensitive to miltefosine. We found that activated forms of both Tac1 and Znc1 confer increased miltefosine resistance, which was dependent on?RTA3?whereas?CDR1?was dispensable. Intriguingly, the induction of?RTA3?expression by miltefosine depended on Znc1, but not Tac1, in contrast to the known Tac1-dependent?RTA3?upregulation by fluphenazine. In line with this observation,?znc1delta mutants were hypersensitive to miltefosine, whereas?tac1delta mutants showed wild-type tolerance. Forced expression of?RTA3?reverted the hypersensitivity of?znc1delta mutants, demonstrating that the hypersensitivity was caused by the inability of the mutants to upregulate?RTA3?in response to the drug. These findings establish Znc1 as a key regulator of miltefosine-induced?RTA3?expression that is important for wild-type miltefosine tolerance.

Key Molecule: Zinc cluster transcription factor Znc1 [2]

• Resistant Disease: Fungal infection [ICD-11: 1F29-1F2F]
• Molecule Alteration: Expression; Up-regulation
• Experimental Note: Revealed Based on the Cell Line Data
• In Vitro Model: SC5314 cells; N.A.; Homo sapiens (Human); N.A.
• Experiment for Drug Resistance: Susceptibility testing
• Mechanism Description: Activating mutations in the ZCFs Mrr1, Tac1, and Upc2 frequently cause acquired resistance to the widely used antifungal drug fluconazole in the pathogenic yeast?Candida albicans. Similar to a hyperactive Tac1, a constitutively active form of the ZCF Znc1 causes increased fluconazole resistance by upregulating the multidrug efflux pump-encoding gene?CDR1. Hyperactive forms of both Tac1 and Znc1 also cause overexpression of?RTA3, which encodes a seven-transmembrane receptor protein involved in the regulation of asymmetric lipid distribution in the plasma membrane.?RTA3?expression is also upregulated by miltefosine, an antiparasitic drug that is active against fungal pathogens and considered for treatment of invasive candidiasis, and?rta3delta mutants are hypersensitive to miltefosine. We found that activated forms of both Tac1 and Znc1 confer increased miltefosine resistance, which was dependent on?RTA3?whereas?CDR1?was dispensable. Intriguingly, the induction of?RTA3?expression by miltefosine depended on Znc1, but not Tac1, in contrast to the known Tac1-dependent?RTA3?upregulation by fluphenazine. In line with this observation,?znc1delta mutants were hypersensitive to miltefosine, whereas?tac1delta mutants showed wild-type tolerance. Forced expression of?RTA3?reverted the hypersensitivity of?znc1delta mutants, demonstrating that the hypersensitivity was caused by the inability of the mutants to upregulate?RTA3?in response to the drug. These findings establish Znc1 as a key regulator of miltefosine-induced?RTA3?expression that is important for wild-type miltefosine tolerance.

Leishmaniasis [ICD-11: 1F54]

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Irregularity in Drug Uptake and Drug Efflux (IDUE)

Key Molecule: Multidrug resistance protein 3 (ABCB4) [1]

• Resistant Disease: Leishmaniasis [ICD-11: 1F54.1]
• Molecule Alteration: Expression; Down-regulation
• 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) [1]

• Resistant Disease: Leishmaniasis [ICD-11: 1F54.1]
• Molecule Alteration: Expression; Down-regulation
• 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) [1]

• Resistant Disease: Leishmaniasis [ICD-11: 1F54.1]
• Molecule Alteration: Expression; Down-regulation
• 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) [1]

• Resistant Disease: Leishmaniasis [ICD-11: 1F54.1]
• Molecule Alteration: Expression; Down-regulation
• 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) [1]

• Resistant Disease: Leishmaniasis [ICD-11: 1F54.1]
• Molecule Alteration: Expression; Down-regulation
• 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) [1]

• Resistant Disease: Leishmaniasis [ICD-11: 1F54.1]
• Molecule Alteration: Expression; Down-regulation
• 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: 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
• Ref 2: The zinc cluster transcription factor Znc1 regulates Rta3-dependent miltefosine resistance in Candida albicans. mSphere. 2024 Jul 30;9(7):e0027024.
• Ref 3: Leishmaniasis and various immunotherapeutic approaches .Parasitology. 2018 Apr;145(4):497-507. doi: 10.1017/S003118201600216X. Epub 2016 Dec 15. 10.1017/S003118201600216X