However, as the mechanisms that regulate BGC expression are complex, genome mining attempts frequently fail and untargeted mutagenesis with physical and chemical mutagens is used – a strategy that is not environmentally friendly. The project leader Sergey Zotchev as well as Olga Sekurova and Anna Stich (Department of Pharmaceutical Sciences), and Martin Zehl (Mass Spectrometry Centre of the University of Vienna) altered together with an international team of scientists DNA polymerase of the model strain Streptomyces lividans to affect DNA replication fidelity. In the strain with such altered polymerase, the mutations arise almost 1000 times as frequently as in the original bacterium. When combining this “mutator” gene with a biosensor for the antibiotic coelimycin (usually not produced by the original strain), Sekurova et al. easily selected mutants where the coelimycin production was activated. The “mutator” could be an alternative to chemical and physical mutagens for drug discovery, acting globally to affect genes that may directly or indirectly influence the production of a desired metabolite.

Publication in Nucleic Acids Research:

Olga N Sekurova, Yi-Qian Sun, Martin Zehl, Christian Rückert, Anna Stich, Tobias Busche, Jörn Kalinowski, Sergey B Zotchev, Coupling of the engineered DNA “mutator” to a biosensor as a new paradigm for activation of silent biosynthetic gene clusters in Streptomyces, Nucleic Acids Research, 2021;, gkab583, https://doi.org/10.1093/nar/gkab583