Biomedical Engineering Reference
In-Depth Information
21.6 RESISTANCE
Treatment of malaria frequently fails because of the development of resistance. In fact, regular
mutations of the parasites force continued development of new drugs. Resistance develops in differ-
ent ways e.g. mutations cause changes in the target proteins preventing interaction with the drug, or
a transport system develops, which decreases the concentration of the drug at the target site.
21.6.1 C
HLOROQUINE
R
ESISTANCE
Chloroquine resistance has been correlated to a mutation in a wild-type food vacuolar membrane
protein termed
P. falciparum
chloroquine resistance transporter (
Pf
CRT). A mutation replacing
Lys76 with Thr enables the protein, in an energy-dependent manner, to transport chloroquine out
of the food vacuole thus, decreasing the chloroquine concentration to below the pharmacologically
active concentration. Other 4-aminoquinolines might also be substrates for the transporter explain-
ing cross resistance. Chloroquine analogs with a modii ed side chain are developed in order to make
analogs, which are not substrates for the transporter.
A number of other hypotheses for resistance including an increased value of the pH in the food
vacuole or prevention of association between chloroquine and heme cannot be excluded.
21.6.2 4-Q
UINOLINEMETHANOL
R
ESISTANCE
The membrane transport
P
-glycoprotein pump,
Pf
MDR1, which is an analog of the mammalian
ABC multidrug-transporter, has a central role in the resistance development of
P. falciparum
para-
sites. An increased number of
Pf
MDR1 transporters facilitate removal of the drug from the putative
target in the cytosol.
21.6.3 A
NTIFOLATE
R
ESISTANCE
Resistance toward antifolate drugs is caused by mutations that alter the active site resulting in dif-
ferent binding afi nities for different drugs. The resistance conferring mutations occur in a stepwise
sequential fashion with a higher level of resistance occurring in the presence of multiple muta-
tions. The decreased afi nity for the drug often is followed with a decreased activity for the natu-
ral substrate, suggesting the parasites containing mutated forms of the enzyme might be selected
against in the absence of drug. Mutation of Ser108 into Asn causes steric interaction between the
Asn side chain and the chlorophenyl group of pyrimethamine and thereby reduces the afi nity of
pyrimethamine to
Pf
DHFR (Figure 21.17). This mutation, however, only causes a moderate loss
of susceptibility to cycloguanil (
21.30
), in which the side chain is shorter. Additional replacement of
Asn51 into Ile results in a higher pyrimethamine resistance but only a moderate effect of cyclogua-
nil. On the contrary, replacement of Ser108 into Thr coupled with Ala16 into Val confers resistance
to cycloguanil but only modest loss of susceptibility to pyrimethamine.
21.7 CONCLUDINGREMARKS
A series of examples of drugs targeting biological systems present only in parasites has been given.
In principle, addressing targets not present in the host but essential for the survival of the parasite
should give a therapy without side effects. Unfortunately, very few drugs are truly selective. Quinine,
as an example, has targets in the parasite cytosol, but does also cause a number of effects in the
patient such as insulin release, inducing severe hypoglycemia, and cardiac arrhythmia. Another
serious problem in the treatment of parasitic diseases is the development of resistance, which is
addressed by giving a combination of drugs. Artemisin and derivatives of artemisinin are given
