Insects: true pioneers in anti-infective therapy and what we can learn from them.

Since the introduction of anti-infectives more than 100 years ago our world has changed: For the first time in human history we were able to combat life-threatening diseases caused by bacteria, fungi, viruses, and protozoa. At least in industrialized countries we are now so familiar with antiinfectives, especially antibiotics, that almost everybody has used them at least once to treat various bacterial infections, which otherwise would have at least taken longer to cure and would have been more painful and severe. However, the golden age of anti-infectives that started in 1950 is coming to an end: Resistance against new antiinfectives, including those representing our last line of defense (e.g. for antibiotics), is emerging dramatically, leading to a return of almost eradicated diseases such as tuberculosis even in industrialized countries. New diseases (e.g. the recent outbreak of swine flu in Mexico or virus-induced severe acute respiratory syndrome, SARS) can spread as rapidly as we can travel, and global warming will allow diseases still regarded as tropical diseases to become endemic in temperate zones. These are only a few—always global—problems of antiinfective therapy. Additionally, as anti-infective research is very expensive and time consuming, several pharmaceutical companies have reduced activity in this important area. These combined factors may lead to a dramatic situation in the very near future similar to that 100 years ago. Our only chance is to continue to fight the microorganisms in order to at least maintain the current status quo. We desperately need new anti-infectives! As natural products, their derivatives, and compounds inspired by natural products have been by far the major source for clinically used anti-infectives, one idea might be to revitalize natural products research as described previously. Here, it might be especially fruitful to consider not only single, free-living organisms as was mainly done in the past (e.g. soil bacteria) but at complex biological systems that consist of (in some cases several) different organisms. With over a million estimated species, insects are the most diverse group of animals on earth and might actually represent 90% of all animal life forms on our planet. Moreover, insects are an ancient class of arthropods; the first primitive members appeared almost 400 million years ago and spread to nearly all environments on our planet. Owing to this high diversity and because of the long time since the first appearance of insects, numerous microorganisms have adapted specifically to insects as hosts and/or food sources. Insects can thus be regarded as a huge reservoir for unusual microorganisms with potential biotechnological and/or pharmaceutical applications. Insects are known as a rich source of bacteria that produce interesting natural products, as highlighted by Paederus bettle symbionts that produce pederin. Moreover, recent reseach indicates that the concept of anti-infective therapy was established in insects millions of years ago: The first example of such a strategy is found in the European beewolf (Philanthus triangulum, Hymenoptera, Crabronidae), a solitary digger wasp that constructs nest burrows in sandy soil. Beewolf females catch and paralyze honeybees and use them as a food source for their larvae in these soil nests. The larvae feed on the bees and spin a cocoon in which they hibernate, until they metamorphose into a new generation of beewolfs the subsequent summer. The brood cell is humid and warm— ideal conditions not only for the larvae but also for the bacteria and fungi that live in the soil and thus could infect and kill the larvae. How are the larvae protected from infection during this long period of time? The answer to this question was presented by Kaltenpoth et al. in 2005: After constructing the brood cell, beewolf females smear a white substance from their antennae onto the ceiling of the cell. This white substance is not less than antibiotic-producing Streptomyces bacteria, which are “cultivated” for this purpose in specialized antennal glands. The deposition of the bacteria dramatically enhances the survival rate of the larvae and also protects the cocoon as the bacteria were also found in the silk. Unfortunately, the nature of the protective compound is yet unknown as the symbiont could not yet be cultivated. The second example was reported by the groups led by Currie and Clardy, who investigated the southern pine beetle [*] Prof. Dr. H. B. Bode Molekulare Biotechnologie, Institut f r Molekulare Biowissenschaften, Goethe Universit t Frankfurt Max-von-Laue-Strasse 9, 60438 Frankfurt am Main (Germany) Fax: (+49)69-798-29557 E-mail: [email protected] Homepage: http://www.uni-frankfurt.de/fb/fb15/institute/inst-3mol-biowiss/AK-Bode