Novel Antibiotic Class Found Active Against Malaria Parasite

Researchers at the University of Pennsylvania (Philadelphia, PA, USA) tested two bacterial amphiphilic antibiotic compounds (BAACs) against P. falciparum. The first of these exhibited an IC50--a measure of the effectiveness of a compound in inhibiting biological or biochemical function--of 200 nmol and cytotoxicity at 40-50 μmol, a 400-fold difference, indicating a potentially high degree of safety. The other BAAC exhibited an IC-50 of 300 nmol and cytotoxicity of 50-100 μmol, a 150-fold difference; both compounds were effective at concentrations well below levels that are toxic to human cells. A parasite related to P. falciparum, Toxoplasma gondii (which causes toxoplasmosis, usually in immunocompromised individuals) was also found to be susceptible to BAACs, with IC50 concentrations in the 3-10 μmol range.

BAAC's are small-molecule non-peptide analogs of natural host defense peptides known as defensins, which are about thirty amino acids in length. Although structurally quite dissimilar, both molecules are facially amphiphilic, meaning they possess several polar, or charged chemical groups on one side of the molecule, and hydrophobic groups on the other side. They are believed to work by inserting themselves inside the lipid bilayers of cells that are deficient in cholesterol, thereby causing the cells to rupture and die. BAACs were originally developed as antibacterial agents; it was then learned that they were active against common pathogenic fungi as well. The study was presented at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held during October 2008 in Washington (DC, USA).

"If we treat for ten hours and remove the compound, the parasites never recover,” said study presenter pharmacologist Doron Greenbaum, Ph.D.

Plasmodium species are responsible for the nearly 500 million cases of malaria worldwide and as many as two million deaths, most of them in children. As with antimicrobial agents, first-line malaria agents are losing effectiveness due to development of resistance to drugs by the target organisms. The complex lifecycle of P. falciparum also makes malaria difficult to treat once it is established. The organism typically enters the body through a mosquito bite, soon takes residence in the liver, and then migrates to red blood cells. It is the last stage that gives rise to the chronic disease known as malaria. During their lifecycle, the organisms take on several distinct morphologic and biological forms.

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