Abstract
The S108N mutation of dihydrofolate reductase (DHFR) renders Plasmodium falciparum malaria parasites resistant to pyrimethamine through steric clash with the rigid side chain of the inhibitor. Inhibitors with flexible side chains can avoid this clash and retain effectiveness against the mutant. However, other mutations such as N108S reversion confer resistance to flexible inhibitors. We designed and synthesized hybrid inhibitors with two structural types in a single molecule, which are effective against both wild-type and multiple mutants of P. falciparum through their selective target binding, as demonstrated by X-ray crystallography. Furthermore, the hybrid inhibitors can forestall the emergence of new resistant mutants, as shown by selection of mutants resistant to hybrid compound BT1 from a diverse PfDHFR random mutant library expressed in a surrogate bacterial system. These results show that it is possible to develop effective antifolate antimalarials to which the range of parasite resistance mutations is greatly reduced.
Highlights
The S108N mutation of dihydrofolate reductase (DHFR) renders Plasmodium falciparum malaria parasites resistant to pyrimethamine through steric clash with the rigid side chain of the inhibitor
Antimalarial drugs have been important tools in the fight against malaria and will be essential in the current effort to eliminate the disease.[1−4] a major problem is the development of parasite resistance to the drugs, which threaten their effective use.[5−9] Plasmodium falciparum parasites resistant to antifolate drugs such as pyrimethamine (Pyr), an inhibitor of parasite dihydrofolate reductase (PfDHFR), and combinations of antifolate and sulfa drugs are widespread throughout malaria endemic regions.[10,11]
The structures of wildtype and mutant PfDHFRs cocomplexes have been solved with inhibitors, namely, WR99210, which can still inhibit mutant enzymes effectively,[18] and Pyr, to which binding has been compromised by PfDHFR mutations
Summary
WR99210-resistant mutants isolated using a bacterial surrogate system are more sensitive to Pyr than Pyr-resistant mutants owing to the presence of wild-type PfDHFR residues S108, N51, C59, and I164.21,22 In general, PfDHFRs can be divided into two series, namely, the “S108 series”, which is sensitive to rigid inhibitors like Pyr but resistant to flexible inhibitors in combination with other mutations, and the “108N series” (or S108N series or N108 series22), which is sensitive to flexible inhibitors but resistant to rigid inhibitors. We hypothesize that the combination of the two types of pharmacophore (rigid and flexible) in a single molecule should be effective against parasites with both types of PfDHFR. We hypothesize that mutations conferring resistance to hybrid inhibitors would be extremely limited owing to constraints on residues in the substrate/inhibitor binding region of PfDHFR. The hybrid inhibitors bind with similar affinities to both types of PfDHFR. They bind in the active site of PfDHFRs in the expected manner, namely, binding with the rigid end to wild-type (S108) PfDHFR and with the flexible end to mutant (S108N) PfDHFR. They should serve as good models for further development of oral antifolate antimalarials, which can forestall further development of mutation-induced resistance
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