Dark, rare and inspirational microbial matter in the extremobiosphere: 16 000 m of bioprospecting campaigns

Abstract

The rationale of our bioprospecting campaigns is that the extremobiosphere, particularly the deep sea and hyper-arid deserts, harbours undiscovered biodiversity that is likely to express novel chemistry and biocatalysts thereby providing opportunities for therapeutic drug and industrial process development. We have focused on actinobacteria because of their frequent role as keystone species in soil ecosystems and their unrivalled track record as a source of bioactive compounds. Population numbers and diversity of actinobacteria in the extremobiosphere are traditionally considered to be low, although they often comprise the dominant bacterial biota. Recent metagenomic evaluation of 'the uncultured microbial majority' has now revealed enormous taxonomic diversity among 'dark' and 'rare' actinobacteria in samples as diverse as sediments from the depths of the Mariana Trench and soils from the heights of the Central Andes. The application of innovative culture and screening options that emphasize rigorous dereplication at each stage of the analysis, and strain prioritization to identify 'gifted' organisms, have been deployed to detect and characterize bioactive hit compounds and sought-after catalysts from this hitherto untapped resource. The rewards include first-in-a-class chemical entities with novel modes of action, as well as a growing microbial seed bank that represents a potentially enormous source of biotechnological and therapeutic innovation.

Extreme environments: microbiology leading to specialized metabolites

“…. It is evident from Tables and that novel species of filamentous actinobacteria and fungi, particularly those isolated from Atacama Desert habitats, are a very good source of new bioactive compounds thereby underpinning the view that these micro‐organisms should feature strongly in bioprospecting campaigns (Bull and Goodfellow ). Substantial improvements in the taxonomic approach to drug discovery can be expected given developments in the classification and identification of eukaryotes and prokaryotes driven by advances in whole‐genome sequencing procedures and associated improvements in bioinformatics as exemplified by Nouiou et al .…”

“…Substantial improvements in the taxonomic approach to drug discovery can be expected given developments in the classification and identification of eukaryotes and prokaryotes driven by advances in whole‐genome sequencing procedures and associated improvements in bioinformatics as exemplified by Nouiou et al . (), increased understanding of the extent of microbial diversity in natural habitats (Bull et al ) coupled with developments designed to provide chemical dereplication (Bull and Goodfellow ).…”

“…In particular, there are good reasons for believing that extremophilic and extremotolerant micro‐organisms will have pride of place in the provision of a new generation of clinically significant drugs thereby preventing a return to preantibiotic days of medicine. However, the success of future bioprospecting campaigns will depend upon access to extreme biomes, notably ones like the Atacama Desert, that are known to be reservoirs of gifted micro‐organisms, especially Actinobacteria and Cyanobacteria (Bull et al ; Goodfellow et al ; Bull and Goodfellow ). However, extreme habitats by their very nature are fragile and hence vulnerable to human activities such as mining and to climate breakdown, as shown by the decimation of microbial communities in hyperarid core areas in the Atacama Desert due to unprecedented rain (Azua‐Bustos et al ) and the melting of permafrost soils (Mackelprang et al ; Hultman et al ).…”

“…Micro‐organisms remain the most promising source of novel specialized (secondary) metabolites as the chemical diversity of these compounds cannot be matched currently by that of chemical libraries (Krug and Müller ) hence the continued interest in the search for new natural products (NP) needed to drive innovative biotechnology (Katz and Baltz ). In recent times, the quest for novel bioactive molecules, especially those that can be developed to control multidrug‐resistant pathogens and treat chronic conditions such as cancer, dementia and epilepsy has been focused on the isolation, characterization (taxonomy) and dereplication (assignment of isolates to taxonomically meaningful groups) of previously unknown micro‐organisms isolated from the extremobiosphere (Bull ; Horikoshi and Bull ; Bull and Goodfellow ).…”

“…These organisms, notably Streptomyces , account for around 70% of known antibiotics, including most of those in clinical use (Newman and Cragg ). The recent discovery that filamentous actinobacteria with large genomes contain many NP‐biosynthetic gene clusters (NP‐BGCs) which express for unknown drug leads partly accounts for the increased focus on these micro‐organisms in bioprospecting campaigns (Bull and Goodfellow ). Especially gifted actinobacteria that have moderate or large genomes (~5·0–7·9 and >8·0 MB respectively) harbour many NP‐BGCs (20–19 and >30 respectively) (Baltz , ; Nouioui et al ) are at the premium in the search for new chemical leads using state‐of‐art‐technologies, such as genome mining (Harvey et al ; Goodfellow et al ).…”