The huge health problem of malaria is exacerbated by the alarming ability of this protozoan to rapidly develop resistance to chemotherapeutic agents. Thus, new antimalarials are desperately needed to bring this deadly disease under control.
In order to identify new drug targets, Istvan and coworkers analyzed P. falciparum mutants resistant to two commonly used antimalarials: thioisoleucine (an analog of isoleucine) and mupirocin (an antibacterial agent used clinically to treat MRSA infections). These two drugs kill blood stage parasites at micromolar and mid-nanomolar concentrations, respectively. For both drugs, increasing the isoleucine concentration in the medium increases the IC50 values (i.e., reduces killing efficiency), suggesting a competitive interaction between isoleucine and both drugs. The kinetics of killing are dissimilar for these two compounds, indicating that they inhibit different isoleucine utilization targets. These results are not surprising since, upon entering red blood cells (“ring stage”), the parasites degrade hemoglobin to obtain a supply of amino acids necessary for replication. Such scavenging is essential because the parasites lack most amino acid biosynthetic pathways. But isoleucine is the only amino acid absent from adult human hemoglobin, hence is the only one that must be obtained from other, less convenient sources.
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