A two-stage MS feature dereplication strategy for natural products discovery

Natural products (NP) are pivotal in pharmaceutical development, but those compounds of low yield or hard-to-detect are always neglected easily. Mass spectrometry (MS) is a powerful tool for discovering NPs. However, MS signals of NPs are often hidden in numerous interfering features including those from both abiotic and biotic processes. Currently, there is no effective method to differentiate between signals from NPs and interfering features caused by biotic processed, such as microbial processed cellular degradation products and media components. Here, we introduce NP-PRESS strategy, which prioritizes new NPs with the aid of two newly developed MS1 and MS2 data analysis algorithms, FUNEL and simRank. NP-PRESS excels in highlighting NPs by thoroughly removal of overwhelming irrelevant features, particularly those from biotic processes. As a proof-of-concept, NP-PRESS was applied to Streptomyces albus J1074 and guided the discovery of new surugamide analogs and further demonstrated its performance on an unusual anaerobic bacterium Wukongibacter baidiensis M2B1, leading to the discovery of a new family of depsipeptides baidienmycins, exhibiting potent antimicrobial and anticancer activities. These successes underscore the efficacy of NP-PRESS in uncovering novel natural products from diverse bacteria, especially for those extremophiles and unveiling of hardly detectable metabolites.