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Heike Brötz-Oesterhelt - searching for novel antibiotics in bacteria

Microbial metabolic products can be used in the fight against dangerous pathogens such as multidrug-resistant bacteria. Since summer 2014, microbiologist Prof. Dr. Heike Brötz-Oesterhelt has been investigating the mechanisms of action of bacterial substances at the University of Tübingen with the aim of paving the way for new antibiotics. Interesting candidates have already been identified.

Prof. Dr. Heike Brötz-Oesterhelt moved from the University of Düsseldorf to the University of Tübingen in 2014. © Hanne Horn

The basic idea is obvious: if several species of bacteria are fighting for dominance in a particular habitat, the one with the best defence strategy will have a greater chance of winning the battle. Substances that are used by bacteria to fight one another could potentially also be used in the medical battle against bacterial infections of humans and animals. Prof. Dr. Heike Brötz-Oesterhelt has been studying such substances since the 1990s. She obtained initial success when she was doing her doctorate at the University of Bonn. In 1998, Brötz-Oesterhelt was awarded two PhD prizes (one from the University of Bonn and one from the Association of General and Applied Microbiology, VAAM) for her achievements in elucidating the mechanism of action of mersacidin. Mersacidin is a peptide antibiotic that is produced by Bacillus strains and belongs to the lantibiotics class. It is active against methicillin-resistant Staphylococcus aureus strains (MRSA) where it prevents the biosynthesis of the cell wall. 

When she was working in industry, Brötz-Oesterhelt discovered a completely new substance class. After her PhD, she joined Bayer HealthCare to study bacteria for their potential use as antibiotics producers. “I inevitably developed a much broader view and looked at several bacterial species rather than just one,” says Brötz-Oesterhelt. Success was not long in coming. Brötz-Oesterhelt and her team discovered so-called acyldepsipeptides (ADEPs), which are produced by soil-dwelling Streptomyces bacteria.

ADEPs drive pathogens into cell death

In conjunction with enzymes (i.e. Clp-ATPases; shown in yellow), ClpP (blue) breaks down proteins (arrow structures) in a controlled manner. ADEPs (red) prevent ATPases from binding to ClpP as well as activating ClpP. This leads to the uncontrolled degradation of vital proteins. © Imran Malik/Heike Brötz-Oesterhelt, University of Tübingen
The mode of action is ingenious. ADEPs can virtually drive bacteria into suicide. All bacterial cells have a protease enzyme called ClpP, which is a natural component of the bacterial recycling machinery that breaks down defective proteins into their constituents and recycles them. ADEPs can interact with these finely regulated mechanisms, resulting in the degradation of defective, as well as intact, vital proteins. When the proteins are required for cell division, bacteria are no longer able to proliferate and they die. This makes ADEPs highly interesting candidates in the development of new antimicrobial agents. When Bayer withdrew from antibiotics research in 2004, Brötz-Oesterhelt initially put her research into ADEPs on the backburner in order to join forces with 20 colleagues and set up a company called AiCuris GmbH & Co. KG in Wuppertal. She became head of the company’s bacteriology division. “The name of the company stands for ‘anti-infective cures’, which was exactly why we founded the company. We established an antibacterial and an antiviral project pipeline. We also initiated a project that focuses on the investigation of drugs that are active against gram-negative bacteria. This project is rather promising and we can soon expect our first human data. I was involved in preclinical drug development until 2010,” says Brötz-Oesterhelt.

Returning to academic research

ADEPs were not entirely uninvolved in her decision to return to academic research. “I would say that ADEPs were my destiny. I wanted to investigate this substance class as thoroughly as possible, but I was unable to do so in industry,” says the microbiologist. She therefore accepted an appointment as professor for pharmaceutical biology at the University of Düsseldorf in 2010. She had already habilitated at the University of Bonn in 2007 when she was still with Bayer HealthCare. In cooperation with researchers from Bonn and Newcastle, Brötz-Oesterhelt was instrumental in elucidating the mode of action that ADEPs use to kill multidrug-resistant pathogens. 

In 2014, Brötz-Oesterhelt moved to Tübingen where she was able to combine research and teaching. She was particularly attracted to Tübingen as she found that the Department for Microbial Bioactive Compounds at the University of Tübingen could offer her something the University of Düsseldorf could not. “Düsseldorf is well positioned as far as structural biology is concerned. However, in Tübingen I am able to work in a larger microbiology network. And I also wanted to teach microbiology again.” Tübingen was a perfect choice for other reasons too; Brötz-Oesterhelt was also able to fit work around family. She is married to a biophysicist and the University of Tübingen offered them a 'dual career couples' solution. Thanks to flexible working hours, the two scientists are able to combine their scientific careers with raising their two children. “The offer came at the perfect time; ten years earlier, I would not have been able to accept the position due to the lack of 'dual career couples' options back then,” said Brötz-Oesterhelt. 

X-ray crystal structure of ClpP: ClpP monomer (left), barrel-shaped active ClpP (right) consisting of 14 subunits (side view and top view). Two ClpP subunits to which an ADEP is bound are shown in a different colour. Binding of ADEPs leads to the opening of the ClpP pore; proteins can enter the barrel where they are degraded.
X-ray crystal structure of ClpP: ClpP monomer (left), barrel-shaped active ClpP (right) consisting of 14 subunits (side view and top view). Two ClpP subunits to which an ADEP is bound are shown in a different colour. Binding of ADEPs leads to the opening of the ClpP pore; proteins can enter the barrel where they are degraded. © Imran Malik/Heike Brötz-Oesterhelt, University of Tübingen

Basic research for combating bacteria

It goes without saying that Brötz-Oesterhelt is still working on ADEPs in Tübingen. “We will work with ADEPs for as long as it takes to clarify key questions,” says Brötz-Oesterhelt. One such question is why ADEPs are more effective against persistent bacteria (i.e. dormant forms of bacteria in the body) than most other antibiotics. The researchers have also discovered that bacteria become easily resistant to ADEPs, and they are interested in finding out why. Brötz-Oesterhelt is also investigating other natural antibiotics, e.g. negamycin, a metabolic product of Streptomyces bacteria. “Negamycin is effective in the animal model, but we have not yet been able to optimise it for use as an antibiotic in human patients. We now aspire to contribute to understanding how this protein synthesis inhibitor works. We are carrying out in vitro experiments to find out how negamycin works and potentially produce derivatives that can be taken up more effectively,” says Brötz-Oesterhelt. 

As far as the therapy of bacterial infections is concerned, she believes that the future lies in using a combination of antibiotics with different modes of action. The researchers hope that this will improve the effect of antibiotics in general, and also reduce the ability of bacteria to become resistant to drugs. “The challenge is to use different medical treatments if required. Antibiotics therapy is not everything. We also need to advance immunostimulatory treatments and vaccines in order to have several strategies for fighting pathogens,” says Brötz-Oesterhelt.

*Sass, P., M. Josten, K. Famulla, G. Schiffer, H.-G. Sahl, L. Hamoen and H. Brötz-Oesterhelt. Antibiotic acyldepsipeptides activate ClpP peptidase to degrade the cell division protein FtsZ. Proc. Natl. Acad. Sci. 108, 17474-17479 (2011)
doi: 10.1073/pnas.1110385108

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