Increasing rates of antibiotic resistance and the burden of natural product rediscovery necessitate the development of strategies to accelerate secondary metabolite discovery. One such strategy is to investigate “neglected” organisms: those without sequenced genomes or characterized metabolism. Herein we report the discovery of streptomonomicin (STM), the first natural product isolated from the neglected halophilic bacterial genus Streptomonospora. STM is an unusually hydrophobic peptide that forms a lasso structure wherein a C-terminal tail is threaded through an N-terminal macrocyclic ring, endowing the molecule with a highly-ordered conformation. Notably, the biological activity of STM stands in contrast to other antibacterial lasso peptides. STM exhibits antibacterial activity against Gram-positive organisms, particularly Bacillus anthracis, the causative agent of anthrax. Bacteria resistant to STM harbor mutations to walR, a gene encoding a response regulator (WalR) that, along with the histidine kinase WalK, forms a two-component signaling system (TCS) involved in cell wall metabolism; the mutants exhibit striking phenotypic defects, including extremely exaggerated chain lengths. Importantly, WalR/WalK is the only known widely-distributed and essential TCS among the Firmicutes and represents an interesting pathway for future drug development efforts. We have also sequenced the first reported Streptomonospora genome, revealing that this growing genus harbors diverse biosynthetic machinery.

Streptomonomicin: An unusual lasso peptide antibiotic from the understudied halophilic actinomycete Streptomonospora alba

249th National Meeting (2015)

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