Ever since the discovery of penicillin in the early 20^th century, we have greatly benefited from natural products produced by microorganisms. Actinomycetes are well known producers of secondary metabolites, as exemplified by antibiotics, and hence are of high pharmacological and industrial interest. From the first reports of streptothricin in 1942 and streptomycin a year later, thousands of naturally occurring antibiotics have been isolated from actinomycetes. Over the past two decades, however, it has become increasingly difficult to obtain new clinically important antibiotics from bacterial sources. In contrast, genome sequencing projects have revealed many biosynthetic gene clusters for the production of unknown secondary metabolites. For example, Streptomyces coelicolor, Streptomyces avermitilis, Streptomyces griseus, and Saccharopolyspora erythraea are known to produce three to five secondary metabolites but actually possess more than 20 clusters that encode known or predicted biosynthetic pathways for secondary metabolites. These findings indicate that actinomycetes harbor the ability to produce many more natural products compared with the ones known currently. The exploitation of such genetic potential in actinomycetes would therefore lead to the isolation of new biologically active secondary metabolites. Our laboratory is therefore trying to develop a method for activating silent or poorly expressed actinomycete genes for synthesizing useful secondary metabolites.
Current results
We recently reported a pragmatic method for activating poorly expressed actinomycete genes for synthesizing a antibiotic by generating a rifampicin-resistant (rif) mutation in the rpoB gene (encoding the RNA polymerase β-subunit) and a streptomycin-resistant (str) mutation in the rpsL gene (encoding the ribosomal protein S12) or both. This led to the discovery of piperidamycin, a novel class of antibiotics from soil-isolated Streptomyces sp. 631689, which normally dose not produce detectable amounts of antibiotics in any type of culture medium. This study shows that modulation of transcriptional and translational apparatus or both (i. e., RNA polymerase and ribosome) effectively activates silent actinomycete genes and can be used to discover numerous new antibiotics.