Changes in the plasmodial surface anion channel reduce leupeptin uptake and can confer drug resistance in Plasmodium falciparum-infected erythrocytes
| Autor: | Michael P. Fay, Margaret Pain, Tetsuya Furuya, Sanjay A. Desai, Xin-zhuan Su, Godfrey Lisk, Shivkumar Kambhampati, Daniel E. Goldberg, Ilya Y. Gluzman |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
Proteases
Cell Membrane Permeability Erythrocytes Leupeptins Genes Protozoan Plasmodium falciparum Drug Resistance Protozoan Proteins Biological Transport Active Cysteine Proteinase Inhibitors In Vitro Techniques Ion Channels Serine chemistry.chemical_compound Antimalarials Mechanisms of Resistance Animals Humans Pharmacology (medical) Malaria Falciparum Pharmacology Serine protease biology Leupeptin biology.organism_classification Cysteine protease Infectious Diseases Biochemistry chemistry biology.protein Cysteine |
| Zdroj: | Antimicrobial agents and chemotherapy. 52(7) |
| ISSN: | 1098-6596 |
| Popis: | Cysteine protease inhibitors kill malaria parasites and are being pursued for development as antimalarial agents. Because they have multiple targets within bloodstream-stage parasites, workers have assumed that resistance to these inhibitors would not be acquired easily. In the present study, we used in vitro selection to generate a parasite resistant to growth inhibition by leupeptin, a broad-profile cysteine and serine protease inhibitor. Resistance was not associated with upregulation of cysteine protease activity, reduced leupeptin sensitivity of this activity, or expression level changes for putative cysteine or serine proteases in the parasite genome. Instead, it was associated with marked changes in the plasmodial surface anion channel (PSAC), an ion channel on infected erythrocytes that functions in nutrient and bulky organic solute uptake. Osmotic fragility measurements, electrophysiological recordings, and leupeptin uptake studies revealed selective reductions in organic solute permeability via PSAC, altered single-channel gating, and reduced inhibitor affinity. These changes yielded significantly reduced leupeptin uptake and could fully account for the acquired resistance. PSAC represents a novel route for the uptake of bulky hydrophilic compounds acting against intraerythrocytic parasite targets. Drug development based on such compounds should proceed cautiously in light of possible resistance development though the selection of PSAC mutants. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|