Omics Technologies to Understand Activation of a Biosynthetic Gene Cluster in Micromonospora sp. WMMB235: Deciphering Keyicin Biosynthesis

Abstract

DNA sequencing of a large collection of bacterial genomes reveals a wealth of orphan biosynthetic gene clusters (BGCs) with no identifiable products. BGC silencing, for those orphan clusters that are truly silent, rather than those whose products have simply evaded detection and cluster correlation, is postulated to result from transcriptional inactivation of these clusters under standard laboratory conditions. Here, we employ a multi-omics approach to demonstrate how interspecies interactions modulate the keyicin producing kyc cluster at the transcriptome level in cocultures of kyc-bearing Micromonospora sp. and a Rhodococcus sp. We further correlate coculture dependent changes in keyicin production to changes in transcriptomic and proteomic profiles and show that these changes are attributable to small molecule signaling consistent with a quorum sensing pathway. In piecing together the various elements underlying keyicin production in coculture, this study highlights how omics technologies can expedite future efforts to understand and exploit silent BGCs.

Natural products in drug discovery: advances and opportunities

“…Metabolomics data can be integrated with data obtained by other omics techniques such as transcriptomics and proteomics and/or with imaging-based screens. For example, Acharya et al used this approach to characterize NP-mediated interactions between a Micromonospora species and a Rhodococcus species 56 . In another interesting example, Kurita et al developed a compound activity mapping platform for the prediction of identities and mechanisms of action of constituents from complex NP extract libraries by integrating cytological profiling 57 with untargeted metabolomics data from a library of extracts 58 , and identified quinocinnolinomycins as a new family of NPs causing endoplasmic reticulum stress 58 (Fig.…”

Label‐free proteomic dissection on dptP‐deletion mutant uncovers dptP involvement in strain growth and daptomycin tolerance of Streptomyces roseosporus

“…Proteomics technology provides a promising exploitation in natural product discovery (Acharya et al ., 2019), post‐translational modification (Sun et al ., 2020), elucidation of biosynthetic pathway (Bordoloi et al ., 2016), even illustration of molecular mechanism response to a certain treatment (Guo et al ., 2019). Specially, LFQ‐based proteomic approach is simple and time saving for sample preparation and result analyses of MS identification and quantification.…”

Synthetic Biology Advanced Natural Product Discovery

“…Efforts to solve these problems are underway [76], including covering the molecular network of large-scale NP extraction libraries with classification information to improve the credibility of annotation, and the development of comprehensive LC-MS/MS databases to support the NP analysis [77]. Acharya's team has used this method to characterize the NP-mediated interaction between different species [78]. In general, molecular networks are mainly used to strengthen the deduplication process to better determine the separation priority of unknown compounds and the elucidation of the relationship between NP analogs, and the rigorous structural elucidation of the NPs of interest also need to be improved.…”