TY - JOUR
T1 - Plasmodium falciparum and Plasmodium vivax demonstrate contrasting chloroquine resistance reversal phenotypes
AU - Wirjanata, Grennady
AU - Handayuni, Irene
AU - Prayoga, Pak
AU - Leonardo, Leo
AU - Apriyanti, Dwi
AU - Trianty, Leily
AU - Wandosa, Ruland
AU - Gobay, Basbak
AU - Kenangalem, Enny
AU - Poespoprodjo, Jeanne Rini
AU - Noviyanti, Rintis
AU - Kyle, Dennis E.
AU - Cheng, Qin
AU - Price, Ric N.
AU - Marfurt, Jutta
PY - 2017/7/25
Y1 - 2017/7/25
N2 - High-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparum and P. vivax. The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In P. falciparum, CQ 50% inhibitory concentrations (IC50s) were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2-fold), or PQ (1.8-fold). The degree of CQ resistance reversal in P. falciparum was highly correlated with CQ susceptibility for all CQRRAs (R2 = 0.951, 0.852, 0.962, and 0.901 for VP, MF, L7, and PQ, respectively), in line with observations in P. falciparum laboratory strains. In contrast, no reduction in the CQ IC50s was observed with any of the CQRRAs in P. vivax, even in those isolates with high chloroquine IC50s. The differential effect of CQRRAs in P. falciparum and P. vivax suggests significant differences in CQ kinetics and, potentially, the likely mechanism of CQ resistance between these two species.
AB - High-grade chloroquine (CQ) resistance has emerged in both Plasmodium falciparum and P. vivax. The aim of the present study was to investigate the phenotypic differences of CQ resistance in both of these species and the ability of known CQ resistance reversal agents (CQRRAs) to alter CQ susceptibility. Between April 2015 and April 2016, the potential of verapamil (VP), mibefradil (MF), L703,606 (L7), and primaquine (PQ) to reverse CQ resistance was assessed in 46 P. falciparum and 34 P. vivax clinical isolates in Papua, Indonesia, where CQ resistance is present in both species, using a modified schizont maturation assay. In P. falciparum, CQ 50% inhibitory concentrations (IC50s) were reduced when CQ was combined with VP (1.4-fold), MF (1.2-fold), L7 (4.2-fold), or PQ (1.8-fold). The degree of CQ resistance reversal in P. falciparum was highly correlated with CQ susceptibility for all CQRRAs (R2 = 0.951, 0.852, 0.962, and 0.901 for VP, MF, L7, and PQ, respectively), in line with observations in P. falciparum laboratory strains. In contrast, no reduction in the CQ IC50s was observed with any of the CQRRAs in P. vivax, even in those isolates with high chloroquine IC50s. The differential effect of CQRRAs in P. falciparum and P. vivax suggests significant differences in CQ kinetics and, potentially, the likely mechanism of CQ resistance between these two species.
KW - Chloroquine
KW - Chloroquine resistance reversal
KW - Drug resistance
KW - Malaria
KW - Plasmodium falciparum
KW - Plasmodium vivax
UR - http://www.scopus.com/inward/record.url?scp=85026372651&partnerID=8YFLogxK
U2 - 10.1128/AAC.00355-17
DO - 10.1128/AAC.00355-17
M3 - Article
C2 - 28533239
AN - SCOPUS:85026372651
VL - 61
SP - 1
EP - 10
JO - Antimicrobial Agents and Chemotherapy
JF - Antimicrobial Agents and Chemotherapy
SN - 0066-4804
IS - 8
M1 - e00355
ER -