|
In vitro resistance to experimental antimalarials |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Blasco B, Leroy D, Fidock DA. Antimalarial drug resistance: linking Plasmodium falciparum parasite biology to the clinic. Nat Med. 2017 23(8):917-928. PMID: 28777791. |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Resistance gene(s) |
|
|
Annotation/Target |
Target location |
Pathway/mechanism |
Selection compound |
Parent strain |
log10 MIR |
IC50 increase |
Genetic changes |
Transcript |
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27432 |
PF3D7_1211900 |
 |
 |
non-SERCA-type Ca2+ -transporting P-ATPase, ATP4 |
Plasma membrane |
Ion homeostasis |
KAE609 |
Dd2 |
<8 (multiple strains) |
2 to 33–fold |
>36 SNPs identified |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27432 |
PF3D7_1211900 |
|
|
non-SERCA-type Ca2+ -transporting P-ATPase, ATP4 |
Plasma membrane |
SJ557733 |
3D7, Dd2 |
7 (3D7) |
3 to 480–fold |
L350H, P412T, V415D |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27432 |
PF3D7_1211900 |
|
|
non-SERCA-type Ca2+ -transporting P-ATPase, ATP4 |
Plasma membrane |
21A092 |
Dd2 |
<9.5 (Dd2) |
20–fold |
V178I |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27436 |
PF3D7_1341900 |
|
|
V-type proton ATPase subunit D, putative |
pH regulation |
pH regulation |
AZ412 |
Dd2 |
<10 (Dd2) |
3 to 6-fold |
G29V |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27439 |
PF3D7_1451100 |
|
|
elongation factor 2 |
Protein synthesis |
Protein synthesis |
DDD107498 |
Dd2, 7G8, 3D7 |
6 (Dd2), 7(7G8, 3D7) |
7 to 5,600–fold |
E134D, E134G and P754S/A, I183T and/or L755F, T185I and S474R, Y186N, S474R, A482T, L755F |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27431 |
PF3D7_0622800 |
|
|
leucine--tRNA ligase, putative |
Protein synthesis |
Protein synthesis |
AN6426 |
Dd2 |
8 (Dd2) |
1.5- to 60-fold |
T400I, V568L, E628G, V630L |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27435 |
PF3D7_1332900 |
|
|
isoleucine--tRNA ligase, putative |
Protein synthesis |
Protein synthesis |
Thiaisoleucine |
3D7 |
nd |
2-fold |
L810F |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27433 |
PF3D7_1213800 |
|
|
prolyl-tRNA synthetase proline--tRNA ligase |
Protein synthesis |
Protein synthesis |
Halofuginone |
Dd2 |
nd |
60- to 360-fold |
L482H/F |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27437 |
PF3D7_1350100 |
|
|
lysine--tRNA ligase |
Protein synthesis |
Protein synthesis |
Cladosporin |
Dd2 |
nd |
6-fold |
Amplification of pfKrs1 |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27427 |
PF3D7_0109800 |
|
|
phenylalanyl-tRNA synthetase alpha subunit |
Protein synthesis |
Protein synthesis |
BRD1095 and BRD7929 |
Dd2 |
BRD7929: >9 (Dd2) |
4- to 84-fold |
M316I, L550V, G512E and V545I |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27438 |
PF3D7_1438500 |
|
|
cleavage and polyadenylation specificity factor subunit 3, putative |
mRNA processing |
mRNA processing |
AN3661 |
Dd2, W2 |
6 (Dd2) |
11–to 200–fold |
H36Y, T406I, Y408S, T409A, D470N, amplification pfcpsf3 |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27443 |
PF3D7_0321900 |
|
|
cyclic amine resistance locus protein |
Transporter of ER/Golgi membrane Mitochondrial transporter |
Transporter of ER/Golgi membrane Mitochondrial transporter |
KAF156 and analogues |
3D7, Dd2 |
8 (Dd2) |
6- to 890-fold |
PfCARL Q821H, P822T, E834D, S1076I/R, I1139K; PfUGT F37V; PfACT A94T, R108K, S110R, D165N, C193*, S242*, L253*, G559K |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27444 |
PF3D7_1113300 |
|
|
UDP-galactose transporter, putative, UGT |
Transporter of ER/Golgi membrane Mitochondrial transporter |
Transporter of ER/Golgi membrane Mitochondrial transporter |
KAF156 and analogues |
3D7, Dd2 |
8 (Dd2) |
6- to 890-fold |
PfCARL Q821H, P822T, E834D, S1076I/R, I1139K; PfUGT F37V; PfACT A94T, R108K, S110R, D165N, C193*, S242*, L253*, G559K |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27445 |
PF3D7_1036800 |
|
|
acetyl-CoA transporter, putative, ACT |
Transporter of ER/Golgi membrane Mitochondrial transporter |
KAF156 and analogues |
3D7, Dd2 |
8 (Dd2) |
6- to 890-fold |
PfCARL Q821H, P822T, E834D, S1076I/R, I1139K; PfUGT F37V; PfACT A94T, R108K, S110R, D165N, C193*, S242*, L253*, G559K |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27428 |
PF3D7_0509800 |
|
|
phosphatidylinositol 4-kinase beta |
Membrane trafficking |
Membrane trafficking |
KAI407 |
Dd2 |
nd |
2- to 10-fold |
H1484Y, amplification of pfpi4k |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
MMV390048 |
Dd2 |
6 (Dd2) |
4- to 5–fold |
S743T, A1319V |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27441 |
mal_mito_3 |
|
|
apocytochrome b (cyb) |
Electron transport |
Electron transport |
ELQ-300 |
Dd2 |
<8 (Dd2) |
24-fold |
I22L |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
Decoquinate |
3D7 |
nd |
90-fold |
A122T and Y126C |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27430 |
PF3D7_0603300 |
|
|
dihydroorotate dehydrogenase |
Pyrimidine biosynthesis |
Pyrimidine biosynthesis |
DSM265 |
Dd2, K1 |
5.3 to 7.3 (Dd2), 8.3 (K1) |
3- to 32-fold |
G181C, amplification of pfdhodh |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27429 |
PF3D7_0523000 |
|
|
multidrug resistance protein 1. MDR1, IP3 receptor |
Unknown |
Unknown |
ATC451840 |
Dd2, 7G8, NF54 |
6 (Dd2), 7 (7G8 and NF54) |
12- to 56-fold |
G316R, M841I, M841I and M924I, A807V/T, Y1076F |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27442 |
PF3D7_API00100 |
|
|
apicoplast ribosomal protein S4 |
Protein synthesis |
Protein synthesis |
Azithromycin |
7G8, Dd2, D10 |
nd |
16- to 17-fold (7G8, Dd2); 57-fold (D10) |
G76V (7G8 and Dd2), G91D (D10) |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27434 |
PF3D7_1225100 |
|
|
isoleucine--tRNA ligase, putative |
Protein synthesis |
Protein synthesis |
Mupirocin |
3D7, HB3 |
nd |
10- to 18-fold |
P1233S |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
| 27440 |
PF3D7_1467300 |
|
|
1-deoxy-D-xylulose 5-phosphate reductoisomerase |
Isoprenoid synthesis |
Isoprenoid synthesis |
Fosmidomycin |
Dd2 |
nd |
8-fold |
Amplification of pfdxr |
 |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
MIR: Minimum inoculum of resistance; SNP: single nucleotide polymorphism; nd: not determined |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
* Whether this is the primary molecular target or the mechanism of resistance remains to be clarified. |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
More information about the selection compound can be found by entering into the particular gene |
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|
|