Mark Pine

Vaccination usually involves injecting someone with a dead or weakened microbe for the purpose stimulating the development of immunity. A similar thing happens when a malaria-infected mosquito bites a human. The mosquito injects a form of the malaria parasite, called a sporozoite, into the person’s blood stream. Only, the human usually doesn’t become immune but sick with malaria.

Suppose there were a way to weaken the malaria parasite after a mosquito bite, so that instead of becoming sick, a person developed immunity. Scientists in Germany, the U.K. and Kenya may have discovered how to do just that. If they are correct, it may be possible to transform mosquitoes from vectors of the disease to vectors of the vaccination.

In an article last month in Science, the medical researchers reported injecting mice with sporozoites of a malaria species that mice are susceptible to. As described yesterday in a broadcast email from ScienceDaily, the scientists then administered the antibiotics clindamycin or azithromycin to the mice for three days. Instead of becoming sick, the rodents developed strong, long-lasting immunity to the parasite.

The methodology worked because of the life cycle of the malaria parasite, Plasmodium. The microbe goes two stages: a stage of sexual reproduction in the insect, which produces the sporozoites, and a stage of asexual reproduction in a human or other mammal, which produces so-called merozoites and causes the disease.

After entering the blood through a mosquito bite, the sporozoites go to the liver, where they mature into merozoites. These forms then leave the liver to infect red blood cells in the bloodstream. About two weeks after the mosquito bite, the infected red cells burst, releasing thousands of merozoites, which in turn infect more red cells. This coincides with the chills, high fever, sweats, headache, nausea and vomiting that characterize the disease. Some of the merozoites created in this stage change back to the sexual form by becoming male and female gametes. A mosquito biting at this time and sucking a blood meal ingests the gametes and the cycle begins again.

In giving the antibiotics to the mice after injecting them with the sporozoites, the scientists interrupted the cycle at the point when the parasite exits the liver. The antibiotics prevented the parasite from invading new cells by destroying an organelle it needs to do so. The parasites were thus forced to remain in the livers of the mice but were unable to invade their blood and cause the disease. But while they remained in the liver, the white cells of the mice were exposed to many of the parasite’s antigens, and the animals developed robust immunity, much as occurs in response to an effective vaccine.

The scientists hope to test their strategy in humans by providing the antibiotics, which are relatively inexpensive, to people in regions where malaria is endemic. Dr. Steffan Borrmann, one of the researchers, said:

The periodic, prophylactic administration of antibiotics to people in malaria regions has the potential to be used as a “needle-free,” natural vaccination.

Until now, efforts to develop a malaria vaccine of the usual kind have not succeeded. On its website, the National Institute of Allergy and Infectious Disease explains, “The complexity of the Plasmodium parasite and the lack of understanding of critical processes, such as host immune protection and disease pathogenesis, have hampered vaccine development efforts.”

If “natural vaccination” for malaria proves effective, would it be possible to use similar strategies to promote immunity to other vector-born diseases by giving prophylactic antibiotics to people in endemic regions?

Two potentially significant advancements in drug therapy—both sought for years—were reported this month: an antibiotic and an anti-obesity drug.

A new potential antibiotic was discussed yesterday in an article in ScienceDaily. It kills a broad group of bacteria, including methacillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant bacteria. At the present time, there is no antibiotic available that is completely effective against these microbes.

Bacterial resistance to antibiotics emerged as a significant problem not long after antibiotics were developed. Resistance to penicillin, which first appeared in 1947, was overcome with the introduction of the penicillin-like compounds, methacillin and oxacillin. But then MRSA, a type of Staphylococcus resistant to those drugs, too, appeared in 1961. Until the 1990s, only one drug, vancomycin, could be counted upon to vanquish the resistant bacteria. But eventually vancomycin-resistant bacteria appeared, too. Despite the development of new antibiotics that work against some resistant organisms (e.g., linezolid), there is none available now that works against all of them.

The newly reported antibiotic was derived from the soil bacterium, Microbispora corallina, and is called microbisporicin. It is effective against MRSA, vancomycin-resistant microorganisms, and another difficult-to-treat bacterium that causes severe diarrhea, Clostridium difficile. Microbisporicin is presently undergoing tests in animals. If it passes the tests, it should move into human clinical trials before long.

Another pharmacotherapy advancement, one that involves a potential anti-obesity drug, was reported earlier this month. The new drug is related to rimonabant (Acomplia, Zimulti, et al.), a weight-loss drug that works by blocking cannabinoid receptors. Activity of the endogenous cannabinoid system of neurons is known to induce hyperphagia in animals, an effect which is perhaps related to the notorious “marijuana munchies” observed in humans. Rimonabant counteracts this effect, and human studies have shown that the drug can produce significant weight loss [pdf file] of up to 7 kg in a year, along with improvements in cholesterol and glucose metabolism. But it was also found that rimonabant is associated with a high rate of severe psychiatric adverse effects, including depression and suicidality. Consequently, the drug was not approved in this country.

The new medication is designated TM38837, because it is not yet named. Christian Elling of the Danish drug company, 7TM Pharma, discussed it at the recent International Congress on Obesity in Stockholm. Although it blocks the same cannabinoid receptors as rimonabant, TM38837 does not cross the blood-brain barrier and penetrate into the brain to the same degree. It apparently acts mainly at receptors in the peripheral nervous system. Elling said the compound has produced significant weight loss in studies in mice and rats. It is hoped that the drug will produce weight loss in human studies, too, and because TM38837 does not act in the brain, it will not have the severe psychiatric adverse effects that prevented approval of rimonabant.

The history of weight-loss drugs shows that most medications were beset with significant problems. As one example, dextroamphetamine (Dexedrine), one of the first drugs prescribed for weight loss, caused insomnia, depression and paranoia, and it was addictive. Another example was the drug combination of phentermine and dexfenfluramine, known as Fen-Phen, which was popular for several years in the 1990s. However, dexfenfluramine was withdrawn from the market in 1997 for causing heart valve defects.

At present there are no substantially effective weight loss medications on the market. If TM38837 demonstrates the efficacy and safety that is hoped for, it could indeed become a breakthrough medication.

Scientists at the University of Illinois have identified a bacterial vulnerability that may permit development of a new class of antibiotics. The weak spot is a group of chemical components of bacterial cell walls that don’t occur in higher animals, making their synthesis a target for new drugs. The components are found in tuberculosis germs and many other bacteria, and they also occur in malaria parasites, raising the possibility of a new treatment for that disease, as well.

In recent decades, the rise of multidrug resistant (MDR) bacteria, including varieties of Staphylococcus and M. tuberculosis, have raised the threat of untreatable infections. Both MDR Staph and MDR TB have been reported in the U.S. Consequently, scientists are searching for new ways to treat infections. The new discovery raises the possibility of a new way to combat these diseases.

The chemical components are isoprenoids, which are biologically synthesized from the chemical isoprene, a small 5-carbon organic molecule, one of the most common compounds found in living organisms. The scientists worked out the structure of the enzyme, IspH, which carries out the synthesis. Then they were able to design a new compound, PPP, that inhibits the enzyme. They reported that the substance is 1000 times more potent an inhibitor than any other known compound. As a result, it may be possible to develop new class of antibiotic drugs based on PPP.

Many years of research and testing, including clinical trials in humans, would be necessary before such drugs could become available. “But,” said Eric Oldfield, the lead scientist, “there are a finite number of proteins unique to bacteria and malaria parasites that can be targeted for the development of new drugs. And everyone agrees that this enzyme, IspH, is a tremendous target.”