Chloroquine resistance in P. falciparum is primarily mediated by mutations in which gene, leading to reduced drug accumulation in the parasite?

Explanation

## Chloroquine Resistance Mechanism **Key Point:** The **pfcrt gene** encodes a chloroquine resistance transporter (CRT) protein that actively pumps chloroquine out of the parasite's digestive vacuole, preventing drug accumulation and reducing efficacy. ## Molecular Basis of Antimalarial Resistance | Gene | Protein | Mechanism | Drug Affected | |---|---|---|---| | **pfcrt** | Chloroquine resistance transporter | Active efflux of chloroquine | Chloroquine | | **pfmdr1** | P-glycoprotein homolog | Reduced drug uptake; amplification confers mefloquine resistance | Mefloquine, Lumefantrine | | **pfdhfr** | Dihydrofolate reductase | Point mutations reduce pyrimethamine binding | Pyrimethamine, Proguanil | | **pfgch1** | GTP cyclohydrolase 1 | Reduced folate synthesis | Sulfonamides, Sulfones | ## Clinical Significance **High-Yield:** The **Asp76Asn and Lys76Thr mutations** in the pfcrt gene are the hallmark of chloroquine resistance in P. falciparum. These mutations alter the charge and structure of the transporter, enhancing chloroquine efflux. **Warning:** Chloroquine resistance emerged in Southeast Asia in the 1950s–60s and has now spread to Africa and South America. Chloroquine is NO LONGER recommended for P. falciparum malaria in endemic regions. **Clinical Pearl:** P. vivax and P. malariae remain largely chloroquine-sensitive, so chloroquine is still used for these species in many regions. **Mnemonic:** **CRT = C**hloroquine **R**esistance **T**ransporter (the pump that kicks chloroquine out)