Microbial Drugs

The majority of the medically important antibiotic drugs (including e.g., penicillins, cephalosporins, erythromycin, vancomycin, and daptomycin) are derived from secondary metabolites, which are produced by bacteria and filamentous fungi. Despite intensive world-wide efforts using alternative approaches based on synthetic chemistry, no other concept could so far surpass the historically successful strategy to exploit biologically active natural products as candidates for anti-infective drugs. The recently observed, increasing resistance of the human pathogens against antibiotics has prompted us to intensify our search for novel lead structures from microorganisms and fungi, which can be used as anti-infective drugs.

Mykologie

The worldwide unique culture collection of myxobacterial natural product producers at the HZI (see Research Group „Microbial Strain Collection, MISG“) has been complemented by the inclusion of additional, promising sources for new anti-infective drugs since 2012. Aside from research on novel eubacterial phylogenetic groups,including the so-called „Rare Actinomycetes“, above all the fungi are now in our focus.

 

Not only the penicillins and cephalosporins , whose discovery had once marked the onset of rnodern antibacterial chemotherapy , but also many other important drugs for use in other pharmaceutical indications have been developed from cultures of filamentous fungi:

Without the discovery of cyclosporins and other immunomodulatory natural products, organ transplant, therapy would certainly not possible to the extent as it is being pacticed today.

The statins ( mevinolin , lovastatin ), from which several highly potent and selective cholesterol-lowering agents have been derived, constitute to date the most commercially successful class of drugs. In recent years, other active ingredients of fungi, such as the pneumocandin derivatives (antimycotics) have been introduced to the market. The antiparasitic agent, emodepside, is one of the most potent anti-parasitic drugs for current use in veterinary medicine. Incidentally, it is up to date the only compound derived from endophytic microorganisms from which a marketed drug has been derived.

 

All of the above compounds are derived from Ascomycota, including their asexual stages. However, even from cultures of Basidiomycota, several biologically active natural products of great practical utility have already been found. The strobilurins are presently the most successful class of fungicides in crop protection , and the derivatives of Pleuromutilin were recently introduced to the market as the first approved anti-bacterial terpenoid antibiotics, initially for the treatment of infections in livestock, as well as as topical antibiotics to combat skin infections in humans.

 

The estimate by David Hawksworth (1991) on the existence of 1.5 million fungal species does not seem to be an exaggeration, according to recent findings of mycological biodiversity research that has been elaborated by modern methods of molekular phylogeny. However, not all fungi can be regarded to be talented secondary metabolite producers; e.g. the Baker's Yeast and its relatives in the Saccharomycetidae , as well as most zygomycetes seem to be devoid of antibiotic agents, except for siderophores. On the other hand, certain groups of Ascomycota and Basidiomycota are extremely creative in terms of secondary metabolite formation. For instance, over 50 different bioactive compounds were obtained from a single strain of Lachnum papyraceum, after a slight modification of the culture conditions; and more than 150 (mostly unknown) secondary metabolites were detected by HPLC-MS in the xylariaceous ascomycete, Hypoxylon fragiforme,  in the course of its life cycle. Cultures of Armillaria mellea and other species of the genus have already yielded no less than 70 different protoilludane orsellinates, which are biosynthesised by a combination of terpenoid and polyketide pathways.

As with the myxobacterial culture collection, our fungi arebeing carefullly pre-selectedfor screening according to criteria arising from the results of modern biodiversity research. However, the in-house isolation work for new fungal strains relies on a global research network, and several collaborations with renowned mycologists, natural product chemists, and research institutes are in place.

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