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DOI: 10.1055/s-0032-1320211
Fermentation development of Pneumocandin B0: the ultimate lead for making Caspofungin
Glarea lozoyensis, the producer fungus, biosynthesizes a family of related compounds. As described in the previous lecture eleven members were isolated and their structures were determined. The major product was named pneumocandin A0. This compound was similar in structure and in biological, (antifungal) activity to echinocandin B, discovered and patented by Eli Lily and company scientists. Due to these similarities it was not clear at that time whether or not pneumocandin A0 could be patented by Merck. An effort was initiated to find a pneumocandin that was significantly structurally unique and to develop a fermentation process to produce it. In the early phases of research it was noticed that one of the pneumocandins had proprietary structure; it was named pneumocandin B0. The wild type G. lozoyensis produced B0 in significantly lower amounts than A0, so the goal of the effort was set to increasing B0 and reducing A0 to assist the isolation and purification of B0. To achieve this, the mutagenesis was used to modify the genetic make-up of G. lozoyensis. This effort was successful and a number of mutants were isolated, latest of which produced B0 as the main product with no detectable A0. G. lozoyensis also produced a positional isomer named pneumocandin C0, which contains 4-HO proline in place of 3-OH-proline found in B0. With mutagenesis and medium modification levels of C0 were reduced to less than 3% compared to B0. In parallel with genetic modification seed and production media were developed to optimize production of pneumocandin B0, increasing its yield several fold over that produced by the wild type G. lozoyensis.