Antimalarial Drug Resistance: A Brief History of Its Spread in Indonesia

Figures & data

Table 1 Antimalarial Drug Mechanism and Resistance Marker

Antimalarial Drug Class	Specific Drug	Mechanism of Action	Site of Action	Genetic Marker of resistance	Reference
Sesquiterpene lactone endoperoxides	Artemisinin	Causes oxidative stress	Endoplasmic reticulum (vesicular structure)	pfk13, pfatpase6	[55–57,59]
	Artesunate			pfk13	[55–57,59]
	Artemether			pfk13	[55,56]
	Dihydroartemisinin			pfk13	[55,56]
Amino alcohol	Quinine	Unclear; thought to interfere with heme detoxification	Digestive vacuole	pfcrt, pfmdr1	[41–43]
	Mefloquine			pfmdr1	[42,110,111]
	Lumefantrine			pfcrt, pfmdr1	[42,112,113]
Antibiotics	Azithromycin	Inhibition of protein synthesis	Apicoplast and mitochondria	Apicoplast rRNA	[44,45,50]
	Clindamycin			Apicoplast encoded 23S rRNA	[17,38,51]
	Doxycycline			Apicoplast rRNA	[38,49]
Antifolate	Pyrimethamine	Inhibition of folate synthesis	Cytosol	pfdhfr	[18,20,36,98,103]
	Sulfadoxine			pfdhps, pvdhps
	Proguanil			pfdhfr, pvdhfr
4-Aminoquinoline	Chloroquine	Interferes hemozoin formation	Digestive vacuole	pfcrt, pfmdr1, pvmdr1	[17,18,20,24,88,91]
	Amodiaquine			pfcrt, pfmdr1	[17,18,20]
	Piperaquine			pfcrt, pfmdr1, plm2 and plm3 amplification	[18,20,21,26]
	Pyronaridine			pfcrt	[20]
	Naphthoquine			Unknown	[20]
8-Aminoquinoline	Primaquine	Unknown	Unknown	Unknown	[18,20]
	Tafenoquine			Unknown
Naphthoquinone	Atovaquone	Inhibition of mitochondrial electron transport (cytochrome b1 complex)	Mitochondria	pfcytb	[18,20,21,35]

Abbreviations: atpase6, adenosine triphosphatase 6; crt, chloroquine-resistance transporter; cytb, cytochrome b; dhfr, dihydrofolate reductase; dhps, dihydropteroate synthase; k13, Plasmodium falciparum Kelch 13; mdr1, multidrug resistance protein; pf, Plasmodium falciparum gene; plm2, plasmepsin 2; plm3, plasmepsin 3; pv, Plasmodium vivax gene; rRNA, ribosomal-Ribonucleic Acid.

Figure 1 Major antimalarial drugs and their tolerance. (A) Hemozoin formation in food vacuoles: (i) 4- aminoquinoles including chloroquine (CQ), amodiaquine (AQ), piperaquine (PPQ), (ii) Amino alcohols including mefloquine (MFQ), lumefantrine (LMF), quinine (QN) and (iii) Artemisinin (ART) bind to reactive heme and interfere its detoxification by making a complex with heme, thus inhibiting the formation of hemozoin. QN and MFQ are sensitive to PfCRT and PfMDR1. Resistance to these drugs occurs by drug mutation and copy number variation in pfcrt and pfmdr1 gene (shown by red diamond). (B) Folate synthetic in the cytosol: Folate synthetic pathway enzymes dihydropteroate synthase is sensitive to the drug sulfadoxine (SDX) and dihydrofolate reductase is sensitive to pyrimethamine (PYR) and proguanil (PRG). Resistance to SDX and PYR occurs due to mutation (shown by red diamond) in dhps and dhfr genes, respectively. (C) Electron transport chain in mitochondria: Atovaquone (ATQ) and ART inhibit cytochrome b complex (CyTb) in the electron transport chain by generating reactive oxygen species. ART in mitochondria causes protein and lipid alkylation, leading to oxidative stress and cellular damage. Resistance to these drugs is caused by a mutation (shown by red diamond) in the cytb gene. (D) Protein synthesis in apicoplast: antibiotics doxycycline (DOX), clindamycin (CLD), and azithromycin (AZT) inhibit protein synthesis by targeting the ribosomal RNA of the apicoplast. CLD resistance is mediated by a point mutation (shown by red diamond) in the apicoplast-encoded 23S rRNA. (E) Endoplasmic reticulum: ART is sensitive to PfATP6 in the endoplasmic reticulum. Variants in Kelch 13 (K13) are the primary mediator ring-stage parasite resistance to ART (shown by red diamond).

Abbreviations: AQ, Amodiaquine; ART, Artemisinin; ATQ, Atovaquone; AZT, Azithromycin; CQ, Chloroquine; CLD, Clindamycin; CyTb, cytochrome b complex; dhfr, dihydrofolate reductase; dhps, dihydropteroate synthase; DOX, Doxycycline; ER, endoplasmic reticulum; K13, Kelch 13; LMF, Lumefantrine; MFQ, Mefloquine; PPQ, Piperaquine; PRG, Proguanil; PYR, Pyrimethamine; QN, Quinine; SDX, Sulphadoxine.

Figure 2 Timeline of chloroquine resistance in Indonesia. This figure summarizes the development of chloroquine resistance in Indonesia from 1974 until 2015 based on their locations and identification methods.

Abbreviations: TES, therapeutic efficacy studies; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism.

Figure 3 Timeline of sulfadoxine–pyrimethamine resistance in Indonesia. The development of sulfadoxine–pyrimethamine resistance in Indonesia was documented from 1979 until 2010. In each instance, the locations and identification methods of resistance are summarized.

Abbreviations: TES, therapeutic efficacy studies; PCR, polymerase chain reaction; RFLP, restriction fragment length polymorphism.

Figure 4 Identification of alleles mutant in PfK13 as an early warning sign for artemisinin resistance in Indonesia. The use of artemisinin combination therapy as a first-line antimalarial drug in Indonesia was summarized from 2015–2019. The polymorphisms of PfK13 serve as a warning sign of resistance toward this drug.

Abbreviation: PCR, polymerase chain reaction.

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