Phenotypic taxonomy and metabolite profiling in microbial drug discovery

Abstract

Microorganisms and in particular actinomycetes and microfungi are known to produce a vast number of bioactive secondary metabolites. For industrially important fungal genera such as Penicillium and Aspergillus the production of these compounds has been demonstrated to be very consistent at the species level. This means that direct metabolite profiling techniques such as direct injection mass spectrometry or NMR can easily be used for chemotyping/metabolomics of strains from both culture collections and natural samples using modern informatics tools. In this review we discuss chemotyping/metabolomics as part of intelligent screening and highlight how it can be used for identification and classification of filamentous fungi and for the discovery of novel compounds when used in combination with modern methods for dereplication. In our opinion such approaches will be important for future effective drug discovery strategies, especially for dereplication of culture collections in order to avoid redundancy in the selection of species. This will maximize the chemical diversity of the microbial natural product libraries that can be generated from fungal collections.

Chemodiversity in the genus Aspergillus

“…For example, the first use of secondary metabolites in Aspergillus taxonomy (Frisvad 1985;Frisvad and Samson 1990;Samson et al 1990) was promising, as was the use of isoenzyme profiling (Cruickshank and Pitt 1990) and the use of simple ecophysiological and nutritional characters (Klich 2002;Pitt and Hocking 2009;Samson et al 2010). It is now well established that profiles of small molecule extrolites are species-specific (Larsen et al 2005;Frisvad 2015). In addition, large molecule extrolites appear also to be species specific .…”

The Chemistry of Griseofulvin

“…The majority of these are found in genus Penicillium, where at least sixteen species are known to be griseofulvin producers, whereas the production is seemingly rare in Aspergillus, as it has only been reported in A. lanosus. 78 Griseofulvin production appears to be very consistent in all the species that have been examined systematically so far and the wide distribution of griseofulvin among filamentous fungi indicates that the biosynthetic capability has been developed at least 13 independent times during evolution. 78 From the middle of the last century and onwards, huge efforts have been made to investigate the biosynthesis of natural products such as griseofulvin using isotope-labeled substrates.…”

“…78 Griseofulvin production appears to be very consistent in all the species that have been examined systematically so far and the wide distribution of griseofulvin among filamentous fungi indicates that the biosynthetic capability has been developed at least 13 independent times during evolution. 78 From the middle of the last century and onwards, huge efforts have been made to investigate the biosynthesis of natural products such as griseofulvin using isotope-labeled substrates. Based on the observations of incorporation of seven units of [1-14 C]acetic acid into griseofulvin, Birch et al in 1958 supported the "acetic acid hypothesis", suggesting that the core ring structure of many phenolic compounds were derived by head-to-tail linkage of acetic acid units.…”

Speradines F–H, Three New Oxindole Alkaloids from the Marine-Derived Fungus <i>Aspergillus oryzae</i>

“…13,14) In our ongoing search for bioactive novel compounds from marine-derived fungi, a strain identified as Aspergillus oryzae was isolated from sediment samples that were collected from the estuary of Min River in China. The chemical study led to the isolation of a novel hexacyclic oxindole alkaloid, speradine F (1), and two novel tetracyclic oxindole alkaloids speradines G (2) and H (3) (Fig. 1), which own structures similar to speradines A-E. 15,16) In this paper, the isolation, structural elucidation and bioactivities of compounds 1-3 are reported.…”

“…1,2) Hence, many pharmaceutical companies and research groups were motivated to start sampling and screening large collections of fungal strains for antibiotic, 2,3) antimycotic, [4][5][6][7] antiviral, 8) antitubercular, 9) anticancerous, 10,11) and other pharmacologically active agents.…”