Saturday, September 24, 2011

Prehistoric proteins may solve antibiotic resistance

Despite the constant arms race between new antibiotic compounds and the evolution of pathogenic bacteria, an ancient protein, that has not been seen on the earth for 59 million years, is shown to be effective against a wide range of multi-resistant bacteria. The proteins, named cathelicidins, were derived from scanning the genome of wallabies and platypus and are part of the innate immune system. This part of our immune system is present from birth and is non-specific: it recognizes general microbial patterns that are common among bacteria and viruses. It contrasts with the adaptive immune system, that generates 'killer cells' and antibody producing cells in response to specific markers on the surface of microbes. The crude proteins of the innate immune system could prove to be effective in killing bacteria that have adapted themselves in order to become resistant against most antibiotic compounds. Because bacterial resistance is becoming a widespread problem, cathelicidins might be the answer to stop it.

The discovery of cathelicidins is part of a project to discover at least ten new antibiotic compounds before the year 2020. 14 genes in the wallaby and 8 genes in the platypus coded for cathelicidins that in lab tests were shown to be efficacious against a broad spectrum of bacteria. The scientists noted a high similarity in these genes, hinting at a common ancestor from which all the cathelicidin genes have evolved. They reverse-engineered the original sequence, and synthesized a protein from the corresponding code. The ancient protein, from an ancestor that lived approximately 59 million years ago, was shown to be highly effective against multiple resistant bacteria: the compound killed 6 out of 7 multi-resistant bacterial strains, and has an efficacy of about 10 to 30 times higher than conventional antibiotics.

These simple, non-specific, immunological molecules are effective because they don't have a specific target. Conventional antibiotics are directed against a specific part of the bacteria. That causes a 'selection pressure' on bacteria, which readily evolve to develop new versions of themselves that don't posses the weakness against the antibiotic to which they were exposed.

Deriving anti-microbial compounds from the simple and crude innate immune system of other animals is not a new idea. Scientists have long sought to find ways of acquiring new antibiotics from animals with a strong innate immune system. These proteins, however, are often found to be toxic for human cells as well. The cathelicidins were found to be safe, which along with their efficacy and capability to kill multi-resistant bacteria, makes them a very promising therapeutic agent.

A characteristic of highly evolved mammals is the ability to launch a pathogen specific immune response. Our body possesses mechanisms to detect 'foreign' molecules, which causes proliferation of T and B lymphocytes, that aim to kill 'non-self' organisms and molecules that enter our body. While the mechanism to distinguish self from non-self is highly sophisticated, the specificity by which the adaptive immune system targets leaves us vulnerable to pathogens that evolve to get rid of whatever it is we use to recognize and kill them. Conventional antibiotics work in the same way: we analyze bacteria for weaknesses we might exploit and develop highly targeted anti-microbial compounds. They respond by getting rid of this weakness. Nowadays, bacteria have found ways to 'stack' resistance, rendering many forms of antibiotics to be ineffective.

Antibiotics-resistant bacteria are said to be one of the biggest problems that medicine will face in the near future. Cathelicidins, with their high efficacy and broad target range seem promising for building new antibiotics. But as current studies have only been conducted in vitro, much more research is needed to prove their efficiency in animals, and after that, in humans.

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