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Vol. 61, Issue 1, 35-42, January 2002
National Institute of Allergy and Infectious Diseases, National
Institutes of Health, Bethesda, Maryland (R.A.C., M.T.F., X.-Z.S.,
J.M., T.N., T.E.W); Department of Chemistry and Program in Tumor
Biology, Lombardi Cancer Center, Georgetown University, Washington DC
(L.M.B.U., P.D.R.); Institute of Pathology, Case Western Reserve
University, Cleveland, Ohio (H.F.); and Department of Microbiology and
Immunology, Albert Einstein College of Medicine, Bronx, New York
(D.A.F.)
Chloroquine resistance (CQR) in Plasmodium falciparum is
associated with multiple mutations in the digestive vacuole membrane protein PfCRT. The chloroquine-sensitive (CQS) 106/1 line of P. falciparum has six of seven PfCRT mutations consistently found in CQR parasites from Asia and Africa. The missing mutation at position
76 (K76T in reported population surveys) may therefore be critical to
CQR. To test this hypothesis, we exposed 106/1 populations
(109-1010 parasites) to a chloroquine (CQ)
concentration lethal to CQS parasites. In multiple independent
experiments, surviving CQR parasites were detected in the cultures
after 28 to 42 days. These parasites showed novel K76N or K76I PfCRT
mutations and corresponding CQ IC50 values that were ~8-
and 12-fold higher than that of the original 106/1 IC50. A
distinctive feature of the K76I line relative to 106/1 parasites was
their greatly increased sensitivity to quinine (QN) but reduced
sensitivity to its enantiomer quinidine (QD), indicative of a unique
stereospecific response not observed in other CQR lines. Furthermore,
verapamil had the remarkable effect of antagonizing the QN response
while potentiating the QD response of K76I parasites. In our
single-step drug selection protocol, the probability of the
simultaneous selection of two specific mutations required for CQR is
extremely small. We conclude that the K76N or K76I change added to the
other pre-existing mutations in the 106/1 PfCRT protein was responsible
for CQR. The various mutations that have now been documented at PfCRT
position 76 (K76T, K76N, K76I) suggest that the loss of lysine is
central to the CQR mechanism.
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