Fermentative production of self-toxic fungal secondary metabolites

Abstract

Fungi are well known for their vast diversity of secondary metabolites that include many life-saving drugs and highly toxic mycotoxins. In general, fungal cultures producing such metabolites are immune to their toxic effects. However, some are known to produce self-toxic compounds that can pose production optimization challenges if the metabolites are needed in large amounts for chemical modification. One such culture, LV-2841, was identified as the lead for one of our exploratory projects. This culture was found to be a slow grower that produced trace amounts of a known metabolite, cercosporamide, under the standard flask fermentation conditions, and extensive medium optimization studies failed to yield higher titers. Poor growth of the culture in liquid media was attributed to the self-toxicity of cercosporamide to the producing organism, and the minimum inhibitory concentration (MIC) of cercosporamide was estimated to be in the range of 8-16 microg/ml. Fermentations carried out in media containing Diaion HP20 resin afforded significantly higher titers of the desired compound. While several examples of resin-based fermentations of soil streptomyces have been published, this approach has rarely been used for fungal fermentations. Over a 100-fold increase in the production titer of cercosporamide, a self-toxic secondary metabolite, was achieved by supplementing the production medium with a commercially available neutral adsorbent resin.

Isolation and characterization of Paenibacillus polymyxa LY214, a camptothecin-producing endophytic bacterium from Camptotheca acuminata

“…According to previous reports that the metal ions, secondary metabolism activators, and extractive resins had effects on the production of natural products [8,9,12,13,19]. In this work, HPLC-DAD quantification [13] and the two known activators salicylic acid (SA) and methyl jasmonate (MeJA) showed slight or adverse effects on CPT production (Fig.…”

Camptothecin-producing endophytic fungus Trichoderma atroviride LY357: isolation, identification, and fermentation conditions optimization for camptothecin production

“…Among them, MeJA is an optimum elicitor in view of that CPT yield increased 3.4-fold. Additionally, end-product feedback inhibition is another common problem during fermentation processes when the concentration of the end product reaches a certain level (Singh et al 2010;Parawira and Tekere 2011). Inclusion of an adsorbent resin in the production medium in combination with extractive fermentation is an effective approach to reduce end-product feedback inhibition and to increase the product titer.…”

“…Inclusion of an adsorbent resin in the production medium in combination with extractive fermentation is an effective approach to reduce end-product feedback inhibition and to increase the product titer. For instance, successes have been made by using HP20 in bacterium fermentation to improve the concentration of anticancer compound thailandepsin A (Liu et al 2012) or to reduce the self-toxicity of the fungal metabolite (Singh et al 2010). We speculated that this approach might be useful to improve CPT yield in LY357.…”

Pilot-plant cultivation of Streptomyces griseus producing homologues of nonactin by precursor-directed biosynthesis and their identification by LC/MS-ESI

“…Because the concentration of a precursor during the fermentation varies in dependence on its dosage intervals, we added into the fermentor adsorbent resin, which keeps the precursor concentration relatively constant by reversibly adsorbing and releasing it. 18,19 The optimum resin concentration in our experiments was 10 g l À1 .…”