Disease Information

General Information of the Disease (ID: DIS00172)

• Name: Falciparum malaria
• ICD: ICD-11: 1F40

Type(s) of Resistant Mechanism of This Disease

  ADTT: Aberration of the Drug's Therapeutic Target

  UAPP: Unusual Activation of Pro-survival Pathway

Drug Resistance Data Categorized by Drug

Approved Drug(s) 3 drug(s) in total

Artesunate

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Unusual Activation of Pro-survival Pathway (UAPP)

Key Molecule: Cysteine desulfurase (K13) [1]

• Resistant Disease: Plasmodium falciparum malaria [ICD-11: 1F40.1]
• Resistant Drug: Artesunate
• Molecule Alteration: Missense mutation; p.C580Y
• Experimental Note: Identified from the Human Clinical Data
• In Vitro Model: Red blood cells; Blood; Homo sapiens (Human); N.A.
• Experiment for Molecule Alteration: Whole genome sequencing assay
• Experiment for Drug Resistance: Giemsa stain assay
• Mechanism Description: All 63 isolates had the K13(C580Y) marker for artemisinin resistance; 79.4% (50/63) had Pfpm2 amplification. K13 mutations confer artemisinin resistance by dampening hemoglobin endocytosis.

Atovaquone

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Cytochrome b (CYB) [2]

• Resistant Disease: Falciparum malaria [ICD-11: 1F40.0]
• Resistant Drug: Atovaquone
• Molecule Alteration: Missense mutation; p.T268C
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Sanger sequencing analysis
• Mechanism Description: Sequencing confirmed Tyr268Cys mutation in the cytochrome b gene, associated with atovaquone resistance, in isolates collected on days 29 and 34 and P. falciparum dihydrofolate reductase mutation Asn51Ile, associated with proguanil resistance in all successfully sequenced samples.

Key Molecule: Cytochrome b (CYB) [2]

• Resistant Disease: Falciparum malaria [ICD-11: 1F40.0]
• Resistant Drug: Atovaquone
• Molecule Alteration: Missense mutation; p.Y268S
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Sanger sequencing analysis
• Mechanism Description: Sequencing confirmed Tyr268Cys mutation in the cytochrome b gene, associated with atovaquone resistance, in isolates collected on days 29 and 34 and P. falciparum dihydrofolate reductase mutation Asn51Ile, associated with proguanil resistance in all successfully sequenced samples.

Proguanil

Drug Resistance Data Categorized by Their Corresponding Mechanisms

Aberration of the Drug's Therapeutic Target (ADTT)

Key Molecule: Bifunctional dihydrofolate reductase-thymidylate synthase (PFDHFR) [2]

• Resistant Disease: Falciparum malaria [ICD-11: 1F40.0]
• Resistant Drug: Proguanil
• Molecule Alteration: Missense mutation; p.N51I
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Sanger sequencing analysis
• Mechanism Description: Sequencing confirmed Tyr268Cys mutation in the cytochrome b gene, associated with atovaquone resistance, in isolates collected on days 29 and 34 and P. falciparum dihydrofolate reductase mutation Asn51Ile, associated with proguanil resistance in all successfully sequenced samples.

Key Molecule: Bifunctional dihydrofolate reductase-thymidylate synthase (PFDHFR) [2]

• Resistant Disease: Falciparum malaria [ICD-11: 1F40.0]
• Resistant Drug: Proguanil
• Molecule Alteration: Missense mutation; p.N51I
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Sanger sequencing analysis
• Mechanism Description: Sequencing confirmed Tyr268Cys mutation in the cytochrome b gene, associated with atovaquone resistance, in isolates collected on days 29 and 34 and P. falciparum dihydrofolate reductase mutation Asn51Ile, associated with proguanil resistance in all successfully sequenced samples.

Key Molecule: Bifunctional dihydrofolate reductase-thymidylate synthase (PFDHFR) [2]

• Resistant Disease: Falciparum malaria [ICD-11: 1F40.0]
• Resistant Drug: Proguanil
• Molecule Alteration: Missense mutation; p.C59R
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Sanger sequencing analysis
• Mechanism Description: Sequencing confirmed Tyr268Cys mutation in the cytochrome b gene, associated with atovaquone resistance, in isolates collected on days 29 and 34 and P. falciparum dihydrofolate reductase mutation Asn51Ile, associated with proguanil resistance in all successfully sequenced samples.

Key Molecule: Bifunctional dihydrofolate reductase-thymidylate synthase (PFDHFR) [2]

• Resistant Disease: Falciparum malaria [ICD-11: 1F40.0]
• Resistant Drug: Proguanil
• Molecule Alteration: Missense mutation; p.S108N
• Experimental Note: Identified from the Human Clinical Data
• Experiment for Molecule Alteration: Sanger sequencing analysis
• Mechanism Description: Sequencing confirmed Tyr268Cys mutation in the cytochrome b gene, associated with atovaquone resistance, in isolates collected on days 29 and 34 and P. falciparum dihydrofolate reductase mutation Asn51Ile, associated with proguanil resistance in all successfully sequenced samples.

References

• Ref 1: Clinical and In Vitro Resistance of Plasmodium falciparum to Artesunate-Amodiaquine in Cambodia .Clin Infect Dis. 2021 Aug 2;73(3):406-413. doi: 10.1093/cid/ciaa628. 10.1093/cid/ciaa628
• Ref 2: Atovaquone/Proguanil Resistance in an Imported Malaria Case in Chile .Am J Trop Med Hyg. 2021 Mar 29;104(5):1811-1813. doi: 10.4269/ajtmh.20-1095. 10.4269/ajtmh.20-1095