Expanding the Ramoplanin Family of Antimicrobial Peptides

Abstract

In the fight against antimicrobial resistance, chemotherapeutic agents derived from natural products have served as a first line of defense. However, widespread antibiotic resistance has created an urgency for the development of new therapeutics. Ramoplanins and enduracidins are first generation nonribosomally-encoded lipodepsipeptides with potent activities against a broad spectrum of Gram-positive pathogens, including those resistant to front line antibiotics. As antimicrobial agents with exciting therapeutic potentials, strategies are warranted to develop access to second generation derivatives to improve drug stability and tolerability. To this end, a targeted genome mining strategy was devised to identify peptide congeners from sequenced bacterial genomes. We identified six biosynthetic gene clusters predicted to produce unique antimicrobial congeners. Two such peptides have been isolated from their native producing strains, Micromonospora chersina strain DSM 44151 and Amycolatopsis orientalis strain DSM 40040, and characterized to expand this class of antibiotics for the first time since the discovery of ramoplanin 30 years ago. We additionally have pursued multidisciplinary strategies to define the activity and selectivity of biosynthetic machinery. Together, this work has provided access to novel peptide scaffolds for further therapeutic development and establishes a platform for antimicrobial discovery and biosynthetic engineering of complex peptide derivatives.