Beating resistant bacteria with the chemical mace

Antibiotics help doctors treat many of the old infectious diseases to which humans are susceptible. However, bacteria have developed a resistance to the old weapons. Researchers at the Helmholtz Centre for Infection Research in Braunschweig are now developing new ones. Around three million people in Europe infect themselves every year with resistant germs against which conventional antibiotics like penicillin are powerless. Some 50,000 of these patients die as a result. The fault often lies in the careless use of antibiotics. In countries like Italy, antibiotics can be obtained from the chemist's, without a prescription. This is why the germs are constantly under selective pressure. If, out of ignorance, the patient does not take the full course of treatment down to the very last tablet, there is a greater probability of resistant germs forming and spreading. As a consequence, in Italy, almost half of the examined infections with streptococcus pneumoniae can no longer be treated with penicillin. And even in Germany, this already applies to some six per cent of infections. In the coming few years, doctors will increasingly stand helpless at the sickbeds, if new antibiotics are not developed quickly - such as archazolid, for example. Dr. Dirk Menche from the Helmholtz Centre for Infection Research in Braunschweig is now transferring the substance obtained from the myxobacterium archangium gephyra to the field of application, because the Young Investigators Group Leader was able to reproduce the antibiotic in the lab. "To date, this is the first and only synthetic pathway," says the chemical scientist with pride, although he did not know for a long time whether the synthetic approach would really succeed as he hoped. Because the complicated molecule is made up of a multiple unsaturated polyketide-macrolactone, a thiazol side chain and eight stereocentres - eight semi-rings with additions. The synthesis is particularly important because the three-dimensional shape of the archazolid is now known.

This is one of the prerequisites for carrying forward this type of antibiotic and for gaining a better understanding of the effects and mechanisms of drug action. So, Menche examines how the shape of the molecule influences its function. This is why he combines structural analysis methods, such as nuclear magnetic resonance (NMR) imaging, with chemical analysis and synthetic methods. However, the synthetic pathway is still too long for industrial production. "Nevertheless, the first informal inquiries have been received from pharmaceuticals companies," says Menche. For archazolid is one of the "most potent and most selective" inhibitors of certain transport proteins, the so-called V-ATpases. These normally supply all kinds of transport processes with energy, through the cell membranes. If they don't work properly, illnesses like osteoporosis, renal acidosis, and even cancer can arise. Because archazolids inhibit the V-ATpases, even low concentrations can prevent growth and division of a whole series of cell types. Menche's research team is now working on simplified but equally potent archazolid variants. "One part of the molecule's side chain is not needed for the biological function and can be omitted," he reports.

Conveniently, Menche's arduously developed synthetic pathway can also be used for other antibiotics. These include, for example, etnangien, which inhibits bacterial RNA polymerase, which is of vital importance to the survival of microbes. Although a drug already exists that combats this RNA polymerase, the bacteria have often become resistant to it - but not to etnangien, says Menche: "Due to our experience with archazolid, we have already been able to develop the first simplified and more stable etnangien variants and have already filed a patent registration for a highly-promising compound."