Silent clusters – speak up!

Microorganisms have provided mankind with a multitude of useful compounds ranging from industrial enzymes to anti-cancer compounds and antibiotics. With the aging population, our need for treatment principles against cancer, Alzheimer's disease and metabolic disorders is increasing. Also, the occurrence and spread of antibiotic resistance in pathogenic microorganisms has become one of our main challenges. For a number of years, it was hoped that our advances in chemical synthesis would provide the desired novelty in terms of scaffolds and targets, however, while there has been success, it has also been realized that the complexity of natural (microbial) products far surpasses anything possible by chemical synthesis. Hence, drug discovery has returned to nature, especially microorganisms, as a source of novel chemistry. Recently, genome sequencing and mining has demonstrated that bioactive compounds hitherto believed to be produced by a eukaryotic organism (a marine sponge) were indeed synthesized by one of the dominant (uncultured) prokaryotes, 'Entotheonella' further underlining the vast bioactive underestimated potential in microorganisms (Wilson et al., 2014). Classical bioassay guided fractionation has been used for decades as the major bioprospecting path, however, this is often a laborious process, and rediscovery of known compounds is a major challenge despite developments in de-replication strategies. The rapidly developing sequencing techniques are introducing sequencing of microbial genomes in almost any microbial research environment , and hence so-called genome mining has become a useful tool in discovery of novel microbial products (Jensen et al., 2014). Despite the complexity of the bioactive secondary metabolites produced by microorganisms , several pathways are conserved at the modular level. This has allowed the development of software, such as ANTISMASH or NAPDOS, which can identify characteristic structures of polyketide and non-ribosomal peptide synthetases (Weber 2014). Such genome mining processes have revealed that the bioactive potential in numerous microorganisms is likely much higher than previously discovered by bioassay-guided fractionation. This has been demonstrated for well-known producers of antibiotics , in Actinobacteria and fungi. However, it is also true for several groups of Gram-negative prokaryotes (Still et al., 2014) that hitherto have not been thought of as useful producers of bioactive compounds. For instance in Pseudoalteromonas luteoviolaceae, 3–4 bioactive compounds have been isolated (violacein, indolmycin, pentabromopseudilin), however, genome mining reveals approximately 15 gene clusters likely encoding for pathways likely producing bioactives (H. Machado, unpublished). It is believed that the reason for the 'non-discovery' of these potential novel compounds is largely because the genes …