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From old to new – the path to the next generation of antibiotics

When they were first discovered, antibiotics were seen as miracle cures. The perception of antibiotics has not greatly changed since. No other class of drugs has ever been able to double the average life expectancy in such a short time. However, there is a huge risk that the success that has been achieved will come to nothing because a growing number of pathogens are becoming resistant to antibiotics.

“Nowadays, more than half of the clinical Staphylococcus aureus isolates are resistant to the antibiotic methicillin,” reports Professor Lutz Heide, head of the Department of Pharmaceutical Biology at the Pharmaceutical Institute of the University of Tübingen. Many other pathogens have also developed resistances to antibiotics.

Prof. Dr. Lutz Heide helps give long-standing antibiotics new powers © Prof. Heide

New antibiotics are continuously required for the control of infectious diseases - however, the number of newly developed antibiotics has been on the decrease over the last few years. More and more pharmaceutical companies have withdrawn from research because the high level of investment required for the development of antibiotics is barely recouped. While a new drug for the treatment of hypertension can, in an ideal scenario, be administered to millions of people over a long period of time, the number of patients requiring any single antibiotic is relatively small. In addition, antibiotics only need to be taken for a limited period of time.

Doctors would only use a new, highly potent antibacterial drug with the utmost reserve, i.e. only in emergencies, in order to prevent the development of resistances for as long as possible. "They may produce the best antibiotic in the world, but are nevertheless unable to dominate the market," said Heide describing the financial dilemma of antibiotic production companies.

Many antibiotics are still waiting to be discovered

The golden age of antibiotics research was between 1940 and 1960. “This was when all the substances that are still used for standard infectious disease treatment were discovered. This includes penicillins, tetracyclins, erythromycin and many others,” says Heide. The majority of these antibiotics are natural substances produced by soil bacteria and fungi. The field of antibiotics discovery still has a great deal to offer. “In soils that have been investigated for specific bacteria, not even one percent of all organisms are known,” said the pharmacist from Tübingen, explaining that the majority of bacteria cannot be cultured in the laboratory and are therefore not available for antibiotics research. “And we’ve only just started to look for potential antibiotics producers among marine bacteria,” affirmed Heide.

These days, researchers can take advantage of the recent progress made in sequencing technologies. The new sequencing devices are extremely rapid and reliable and they will very soon be able to produce a huge amount of data. “The complete DNA sequences of bacteria that could not previously be cultured will also be available very soon,” said Heide with some measure of confidence. Considering that the majority of soil bacteria can produce ten, sometimes even 20, different antibiotics, then we don’t have to worry about the future of this particular field of research. Heide also believes that "in nature, there is a huge number of antibacterial substances that are still to be discovered".

Soil bacteria of the genus Streptomyces produce numerous antibiotics. © Prof. Heide / University of Tübingen

Discarded antibiotics are coming back into fashion

Heide and his colleagues not only aim to identify completely new antibiotics; they also want to give already known antibiotics, identified in the genus Streptomyces more than forty years ago, new power using genetic engineering methods. “By inhibiting the gyrase enzyme, the aminocoumarins very effectively prevent the duplication of genetic information and cell division in bacteria,” said Heide explaining the mechanism of action. However, of all substances in this substance class, only novobiocin reached clinical application, where, however, it has never played a huge role due to numerous side effects and a limited pathogen spectrum.

Genetic engineering of new antibiotics using soil-dwelling Streptomyces roseochromogenes bacteria. © Heide / University of Tübingen

The fact that aminocoumarins are becoming higher profile is, amongst other things, due to their effect on a growing number of methicillin-resistant Staphylococcus aureus strains. "We are trying to create new aminocoumarin derivates by specifically modifying individual chemical structures. These new aminocoumarins will then have better pharmacological properties and a broader spectrum of activity than novobiocin, for example," said Heide who is also part of the SFB (collaborative research centre) 766 in Tübingen (The bacterial cell envelope). Heide's approach, involving using an antibiotic that had fallen into oblivion and optimising it with genetic engineering methods, has its advantages. The aminocoumarins have already been tested for their human compatibility in clinical trials - otherwise novobiocin would not have been approved for sale. "A completely new antibiotics class always carries the risk of being too toxic. This is the case for example when the substance not only attacks bacteria but also human cells," said Heide.

Technique is also suitable for other drugs

In the meantime, Heide and his colleagues have produced more than 130 aminocoumarin derivates, and many more are to follow. “Some of these new substances have at least the same potential as novobiocin,” said Heide, who is clearly pleased with their findings. However, the researchers are not just focused on developing the best possible antibiotic. They consider it far more important to show that their technique actually works, as Heide is already looking beyond his own field of research. "In future, this method will not only enable us to optimise antibiotics for human application, but also a broad range of other natural substances – for example the important group of cytostatic drugs."

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