28.11.2017 08:02

Publication in ACS Infectious Diseases

Anti-tuberculosis drug from African medicinal plant endophyte

Endophytic fungi are a very promising source of new active substances. An interdisciplinary team of researchers in Düsseldorf has identified and isolated the new agent chlorflavonin, which shows a previously unknown mode of action against tuberculosis. They have now published their results, which were produced in the framework of Research Training Group 2158, in the scientific journal American Chemical Society – Infectious Diseases.<

Caption: Culture of endophytic fungi Mucor irregularis. (Photo: Linda Wiegand / HHU)

Endophytic fungi live inside plants. They feed on the plants’ nutrients, but they also protect their host organisms, for example by forming antibacterial or other protective substances. That is why these fungi have attracted increasing attention in recent years in the area of drug research, since they partly form substances that have quite a different effect and with which new therapeutic strategies can be developed to treat diseases. Pharmacists in the research group led by Professor Peter Proksch (IPBB - Institute of Pharmaceutical Biology and Biotechnology) are also now studying these fungi in greater depth.

Many of his junior researchers are from abroad. “When they come to Düsseldorf, we ask our new doctoral researchers to bring medicinal plants from their home countries with them,” says Professor Proksch. Then they work on these plants in Düsseldorf, study their active ingredients and isolate the bioactive compounds. Professor Proksch continues: “This approach is also very important when the researchers return home, since their research work has a regional bearing and thus a greater degree of acceptance at local level.” 

Herve Sergi Akone, a former doctoral researcher from Cameroon, brought with him Moringa stenopetala, a medicinal plant used in traditional medicine in his home country. He also undertook trips back home, which were sponsored by the German Academic Exchange Service, during his doctoral studies in order to collect further material. Dr. Akone, who has meanwhile completed his doctoral degree at HHU, extracted the endophytic fungus Mucor irregularis from the plant and from this, in turn, an active substance known as chlorflavonin. Its antimicrobial effect was tested by Nidja Rehberg, a doctoral researcher in the working group led by Professor Rainer Kalscheuer (also IPBB). In a multi-stage process, to which several different groups affiliated to RTG 2158 contributed, the substance was purified and tested regarding its spectrum of activity. It was shown that chlorflavonin has a specific antibacterial effect on the tuberculosis pathogen Mycobacterium tuberculosis. The corresponding tests were carried out on virulent strains of this pathogen in the high-security laboratory at the Institute of Medical Microbiology and Hospital Hygiene (Director: Professor Klaus Pfeffer).

In further steps, the researchers successfully detected where and how the active substance acts against the tuberculosis pathogen: The production of important amino acids in the pathogen is inhibited, which prevents its metabolism and reproduction. What is particularly significant is that chlorflavonin also acts against multi-resistant and extremely resistant strains of Mycobacterium tuberculosis – what are known as XDR isolates. These are becoming more and more of a problem, not least because the last new anti-tuberculosis drugs were developed in the 1970s. Treatment today is very lengthy, complicated and accompanied by many side effects: Patients must take four different types of medication over at least six months. Above all in poorer countries, this costly treatment is often not kept up but instead in many cases abandoned when the symptoms disappear.

That is why it is all the more important to find new active substances which work differently from the old ingredients in order to prevent a build-up of resistance. It is precisely here that chlorflavonin is breaking new ground and furthermore works together very well in combination with certain other clinical anti-tuberculosis drugs. “It might be possible to reduce treatment time considerably, which can have a positive impact on cost and the patient’s motivation,” hopes Professor Kalscheuer.

Chlorflavonin is a member of a substance group uncommon in fungi; it is usually found in plants. How exactly it works has been unveiled using computer models at the Institute for Pharmaceutical and Medicinal Chemistry (Professor Holger Gohlke’s working group). Where the substance docks onto the Mycobacterium tuberculosis is now known. The computer can also be used to test how the basic substance originating from the fungi can be modified so that it docks onto the target structure better and is thus most effective. “On the basis of a lead compound, a whole library of different derivates can be developed that can display better absorption, metabolisation or pharmacokinetics properties,” says Professor Proksch, summarising the next tasks.

Research Training Group 2158

Research Training Group 2158, “Natural products and natural product analogs against therapy-resistant tumors and microorganisms: new lead structures and modes of action”, which is funded by the German Research Foundation, was launched in 2016. Within the RTG, interdisciplinary teams from medicine, pharmacy, chemistry and biochemistry are searching for new active ingredients on the basis of naturally occurring substances.

The members of the Research Training Group are gaining an insight into the whole modern drug development chain up to and including new pharmaceutical lead structures. This ranges from the search for potential drug candidates in organisms such as plants, animals or fungi to testing the substances for their possible effects, for example as antibiotics or to fight tumours, and to structure elucidation and chemical synthesis. As a result, the junior researchers who have earned their doctoral degree within the RTG have enjoyed very broad-based training and are ideally qualified for further employment in drug research, the pharmaceutical industry and clinical pharmacology.

25 doctoral researchers are currently working in 14 different groups affiliated to the Research Training Group. Apart from research in their respective groups, they all have a common curriculum that includes joint lectures, work in various laboratories as well as excursions to industrial enterprises.

Original publication

N. Rehberg, H. S. Akone, T. R. Iorger, G. Erlenkamp, G. Daletos, H. Gohlke, P. Proksch & R. Kalscheuer, Chlorflavonin targets acetohydroxyacid synthase catalytic subunit IlvB1 for synergistic killing of Mycobacterium tuberculosis, ACS Infectious Diseases, 6 November 2017 (online)

DOI: 10.1021/acsinfecdis.7b00055

Online: pubs.acs.org/doi/abs/10.1021/acsinfecdis.7b00055

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