From natural products discovery to commercialization: a success story

Abstract

In order for a natural product to become a commercial reality, laboratory improvement of its production process is a necessity since titers produced by wild strains could never compete with the power of synthetic chemistry. Strain improvement by mutagenesis has been a major success. It has mainly been carried out by "brute force" screening or selection, but modern genetic technologies have entered the scene in recent years. For every new strain developed genetically, there is further opportunity to raise titers by medium modifications. Of major interest has been the nutritional control by induction, as well as inhibition and repression by sources of carbon, nitrogen, phosphate and end products. Both strain improvement and nutritional modification contribute to the new process, which is then scaled up by biochemical engineers into pilot scale and later into factory size fermentors.

Thoughts and facts about antibiotics: Where we are now and where we are heading

“…There are cases of a single metabolite, such as brefeldin, exhibiting 10-15 different bioactivities due to having multiple binding sites on host cells. [57][58][59] Finally, natural products generally meet the requirements of green chemistry.…”

Enhancing production of a 24-membered ring macrolide compound by a marine bacterium using response surface methodology

“…It was also proven in some literature that the preferred carbon source for the production of secondary metabolites was starch (Syed et al, 2009). Ammonium salts are usually repressive for secondary metabolites fermentation (Demain, 2006). As shown in Figs.…”

“…F. bombycis can be seen as a slowly utilized organic nitrogen source for a high content of proteins. Inorganic nitrogen sources, such as ammonium salts, are rapidly utilized, which makes them optimal for growth but is usually repressive for secondary metabolite biosynthesis (Demain, 2006). So, the combination of slowly (F. bombycis) and rapidly (ammonium salts) utilized nitrogen sources is optimal for macrolactin A production.…”

Engineering of the methylmalonyl-CoA metabolite node of Saccharopolyspora erythraea for increased erythromycin production

“…A critical aspect of this process is that industrial microorganisms must often be genetically improved for higher production before they can be used commercially (Parekh et al, 2000). The success of a strain improvement program can determine whether a new natural product goes to market or is abandoned (Demain, 2006). For generic drugs, strain improvement determines which manufacturer maintains the greatest market share.…”