Application of NMR-based Metabolomics for the discovery of novel antibiotics produced by 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 [1]  For this purpose, we have built up an actinomycete strain collection from remote areas (more than 800 strains), in which we sought to activate the production of poorly expressed antibiotics using specific eliciting compounds or growth conditions [2] 

Due to the high rediscovery rate of known antibiotics by conventional approaches such as bioassay-guided separation, NMR-based metabolomics was developed for application to antibiotic discovery. Application of the technology includes determining the media- and time-dependent antibiotic production profiles for promising producer organisms and identifying the antibiotics that are elicited through ecological, chemical or genetic perturbation. The NMR spectral data were interrogated statistically using several multivariate data analyses to differentiate chemical profiles and correlate specific NMR signals to bioactivity. Quantitative metabolomics allows efficient identification of candidate molecules and avoid chemical redundancy. Proof of concept is presented, including the identification of 7-prenylisatin and a highly methoxylated isocoumarin by streptomycetes from our strain collection.

References

1         Payne, D.J. et al. (2007) Drugs for bad bugs: confronting the challenges of antibacterial discovery. Nat. Rev. Drug Discov. 6, 29–40

2         Zhu, H. et al. (2014) Eliciting antibiotics active against the ESKAPE pathogens in a collection of actinomycetes isolated from mountain soils. Microbiology 160, 1714–1725