Andreas Kirschning from Leibniz University Hannover, Germany, explains how genetically modified microbes offer a short-cut to valuable derivatives of natural products

Nature's reservoir of diverse natural products seems to be endless. Increasing numbers of new and highly complex metabolites - the chemical byproducts that result from metabolism - are being discovered all the time and evaluated for their use in medicine as antiinfectives, immunosuppressants and in cancer therapy. 

Many natural products are produced by microbes in the form of secondary metabolites. Although these compounds might have properties that are potentially useful to humans, they are not designed by intention to meet these demands. As a consequence, even though the main structure of a natural product might harbour highly potent biological activity, other characteristics, such as its low solubility in water, could render it useless for any biomedical application. 

While this might suggest that researchers should be strengthening their efforts to invest in huge screening programs to access what kind of diversity Nature still has to offer, a different path, one that is deeply ingrained in human nature, can be chosen: to learn, to change and to improve.

The increasingly sophisticated toolbox of organic chemistry offers the means for the latter option. Keeping what is needed for a natural product's biological activity while changing things that might improve its unwanted characteristics, such as insolubility, is usually achieved in two different ways. 

 

Fermentation flasks are used to cultivate the mutant microbes

 

Firstly, even highly complex natural products can be completely artificially prepared by chemical total synthesis, starting with simple building blocks. While in the process of constructing a whole metabolite from scratch, modifications can be incorporated that can successfully alter unwanted characteristics. Alternatively, the native natural product can be prepared or isolated and then chemically modified to meet target demands. Termed semisynthesis, this approach allows access to small compound libraries, but it is limited to certain types of modifications by the respective natural product's stability and reactivity profile. In contrast, total synthesis can lead to any modification one can think of but it is often impractical or too cumbersome for screening programs.

However, a third way of obtaining modified natural products has arisen in recent years with the development of sophisticated methods of metabolic engineering. This strategy combines chemical synthesis with genetic engineering. Refined insights into the intricate ways in which living organisms make natural products - termed biosynthesis - have made it possible to genetically engineer microbial mutants, which are unable to generate the essential building blocks required for assembly of a particular natural product. Disrupting the biosynthesis of the natural product in this way can open doors to the biosynthesis of other 'unnatural' products.

While the biosynthesis of natural products is known to be a highly selective and efficient process, it has been shown that certain degrees of flexibility do exist in these finely tuned assembly line systems. This flexibility can be exploited by feeding chemically prepared modified natural building blocks to the mutant microbes, leading to novel natural product derivatives. These compounds might already have the desired characteristics, or may be more suitable for further modifications than the natural product itself. This concept is known as mutational biosynthesis, or mutasynthesis.

It has to be noted that the intricacies of biosynthetic pathways are not fully understood yet and in the past many mutasynthetic approaches were far from being practical in terms of productivity. That said, mutasynthesis has huge potential to provide short-cut access to natural products and derivatives of choice. 

Andreas Kirschning

Read Andreas Kirschning's Perspective article on mutasynthesis in issue 20, 2007 of  Organic & Biomolecular Chemistry.