Microbial Drugs

The majority of the medically important antibiotic drugs are derived from secondary metabolites, which are produced by bacteria and filamentous fungi. Despite intensive world-wide efforts using alternative approaches, 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.

Leader

Fermentation

The biotechnology team in the "Microbial Drugs" department is responsible for the production of anti-infective candidates. This includes the production in technical scale (up to 350 L working volume), process development as well as optimization of up- and downstream processes. The aim is to provide promising bioactive agents in sufficient quantity and quality for inter alia hit-to-lead optimization, formulation development and preclinical studies.

In the upstream processing, natural products will be typically produced by filamentous microorganisms (myxobacteria, actinomycetes, fungi, etc.). Recombinant production strains are also being investigated on a regular basis. The focus is the development of new processes or optimization of existing processes from strain development via pre-culture management to pilot scale. The process management is prioritized towards the following objectives:

  • Production of new secondary metabolites, which showed promising biological activities, for the structure elucidation and for mode of action studies.
  • Production of already known secondary metabolites with new, interesting properties.
  • Production of secondary metabolites for co-operation partners in research and industry.
  • Bioprocess development for the reduction of side products along with an optimized space-time yield.
  • Optimisation of fermentation processes and product purification to increase yields.
  • Scale-up of production processes to pilot plant scale.

To realize the large number of different, often not ell characterized, producer strains, a high degree of flexibility for the equipment and the personnel is necessary. Bioreactors with a working volume of between 1.5 liters (laboratory scale) and 350 liters (pilot plant scale) are available. Cultivation can be carried out in a batch, feed-batch, semi-continuous, or continuous mode depending on the process. All bioreactors can be operated as stirred tank to recirculation reactor. Furthermore, instrumented shake flasks allow a more precise transfer of the fermentation from the shake flask to the bioreactor.

Parameters for mass balancing and detailed characterization the processes (e.g. offgas analysis, pH value, temperature, dissolved oxygen) are measured continuously (online). Substrate consumption and product formation are analyzed with chemical, enzymatic and HPLC methods.

Fermentation broths can be purified in-house. Product quality and quantity are depend on requirements and specifications. Similar to fermentation, purification processes are developed in laboratory scale and gradually scaled up. The aim is to develop processes that can be applied to industry in the future. The aim is to minimize product losses and purification steps while maintaining the same quality.

Typically, purification begins with the biomass separation using a semi-continuous centrifugation or various process filters. Devices can also be operated in combination. Solid and liquid extractions will be carried out on a preparative scale in the existing explosion protection area. Extracts are concentrated with a large-scale rotary evaporator. Fine purification is carried out chromatographically. A selection of different columns and chromatographic systems are available for this purpose. Purified substances are made available to our partners in the Helmholtz associated network and the German Centre for Infection Research.

Story: New drugs from fungi

HZI researchers traveled to Yaoundé, Cameroon, for a workshop on the collection, culture and identification of fungal strains. A new research hub will strengthen natural product research in fungi in the country. [read more]

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Video

  • How do researchers at the HZI and HIPS develop antibiotic candidates from natural products?

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