The generation of a chromatogram-simplified Streptomyces albus S4 heterologous host and the activation and characterisation of surugamide biosynthesis in S. albus S4

The rise in antimicrobial resistance combined with the decline in antibiotic discovery has put antibiotic therapy at risk. As a result, there is an urgent need for new antibiotics. Microbial secondary metabolites are a major source of industrially and medically significant compounds. Most of the antibiotics used in the clinic are derived from secondary metabolites produced by streptomycetes. Even though streptomycetes were thought to be mined to exhaustion, advances in genome sequencing and genome mining has revealed the presence of the untapped wealth of secondary metabolite encoding biosynthetic gene clusters harboured in their genomes. Developing strategies to awaken these silent gene clusters along with understanding the biosynthesis of these natural products is therefore of great importance.

In this work, five gene clusters were targeted in S. albus S4 to generate a new heterologous host, which is hoped to aid in the research efforts for new antimicrobials. Activation of silent gene clusters hold great potential in the discovery of new and useful compounds. The genome of S. albus S4 harbours many silent gene clusters. In this study, pleiotropic approaches were used to switch on the production of an antibacterial compound(s) in S. albus S4. Bioinformatic analyses of the spectral data obtained from the chemical extracts identified surugamides within the chemical extract. As surugamide A was previously reported to have antibacterial activity, its bioactivity profile was further investigated. Surugamides belong to the family of non-ribosomal peptides. Non-ribosomal peptides constitute a major class of natural products with diverse activities ranging from antibacterials to immunosuppressants. Atypical to canonical non-ribosomal peptide synthetase systems, the surugamide gene cluster lacks a cis-acting release mechanism responsible for the release of the cyclic and linear peptides it encodes the production for. In this work, a trans-acting standalone release factor was identified and its in vitro activity was also investigated.