Idenfication and isolation of novel antibiotic prodrugs from rare actinomycetes

Infections caused by growing multiple drug-resistant (MDR) bacteria continue to be an emerging world-wide intractable problem. Searching for new antibiotics to combat MDR human pathogens is therefore of utmost urgency. The aim of this research is to find novel antibiotics from resourceful microorganisms. Actinomycetes are a prominent source of important secondary metabolites, and produce some 70% of all antibiotics currently in use. Genome sequencing revealed that these bacteria have more potential for secondary metabolite production than previously believed. Therefore, new efforts are being made to exploit actinomycetes to discover antibiotics with a new mode of action. Our research focuses on a collection of actinomycetes from remote mountain areas, in which we seek to activate the production of poorly expressed antibiotics using specific eliciting compounds or growth conditions. Many of the actinomycetes were found to produce antibiotics targeting MDR pathogens of the ESKAPE category, typically under particular growth conditions. NMR-based metabolomics was applied here for prioritizing actinomycetes for further discovery efforts, identifying the optimal production media and harvesting time, and for the rapid identification of the bioactive components, as well as microbial biotransformation. The NMR data were supported by statistical and multivariate data analysis to readily identify the peaks belonging to the bioactive components. By this routine, elven new antibiotics compassing disparate structural motif were discovered, such as phenazine, angucycline, etc. Following the elucidation of novel compounds, growth conditions were optimized for better production by the actinomycetes.

Keywords: actinomycetes, new antibiotics, NMR, metabolomics