Novel Antibiotic Class Also Active against Malaria Parasite

A new class of antimicrobial agent with broad-spectrum activity has been found to also kill Plasmodium falciparum, the parasite that causes the most lethal form of human malaria. University of Pennsylvania pharmacologist Doron Greenbaum, Ph.D., presented these results, from in vitro experiments, at the recent 48th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held in Washington, D.C. Dr. Greenbaum reported that small molecule defensin-mimetic compounds discovered by Radnor, Penn.-based biopharmaceutical company PolyMedix, irreversibly kill P.falciparum while sparing human red blood cells. 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 anti-microbial agents, first-line malaria agents are losing effectiveness due to development of resistance to drugs by the target organisms.

Dr. Greenbaum demonstrated that PolyMedix’s compounds kill P.falciparum irreversibly, meaning the cells do not recover when the agent is depleted. Irreversible killing distinguishes a “cidal,” or true killing mechanism, from a “static” mechanism that holds the infectious agent at bay while the body’s immune system fights off the infection. “If we treat for ten hours and remove the compound, the parasites never recover,” notes Dr. Greenbaum. Many antimicrobial and antifungal drugs are of the static variety.

The two PolyMedix compounds tested against P.falciparum are effective at concentrations well below levels that are toxic to human cells. One of the test compounds exhibited an IC50 against P.falciparum of 200nM and cytotoxicity at 40-50μM – a 400-fold difference indicating a potentially high degree of safety.

Numbers for the other compounds were 300nM and 50-100μM, a 150-fold difference that is also quite good for an anti-infective drug. A parasite related to P.falciparum, T.gondii, is also susceptible to the compounds, with IC50 concentrations in the 3-10μM range. T.gondii causes toxoplasmosis, usually in immunocompromised individuals.

The complex lifecycle of P.falciparum 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. PolyMedix’s defensin-mimetics show very high killing efficacy against all stages of red cell infection. The next step is to see if the compounds can clear infection in a mouse model, in the liver phase as well as the red cell stage.

PolyMedix antibiotics are small-molecule non-peptide analogs of natural host defense peptides that higher animals use to fight infections. In humans these molecules, known as defensins, are about thirty amino acids in length. Although structurally quite dissimilar, defensins and PolyMedix’s compounds share a common characteristic that is responsible for their anti-infective activity. 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. Therefore these molecules kill pathogens by targeting membranes rather than proteins. Dr. Greenbaum hypothesizes that this mechanism is employed against both bacteria and Plasmodium.

Peptide anti-infectives suffer from serious drawbacks, including poor pharmacokinetics, tissue penetration, and distribution, inadequate safety to efficacy ratios, and difficulty of manufacture. Small-molecule mimics such as PolyMedix’s can be designed for optimal distribution, pharmacokinetics, and efficacy and are generally easier to discover and study. PolyMedix originally developed these compounds as antibacterial agents. It was then learned that they were active against common pathogenic fungi as well. Most anti-infectives work against one class of infectious agent. PolyMedix’s compounds are the only pharmacologically relevant molecules that show significant activity against three.

PolyMedix’s lead defensin-mimetic antibiotic compound, PMX-30063, is currently in Phase I human clinical testing, and is intended to be developed as a broad anti-Staph agent.

Source: PolyMedix