Dissolution of the Disparate: Co-ordinate Regulation in Antibiotic Biosynthesis

Abstract

Discovering new antibiotics is vital to combat the growing threat of antimicrobial resistance. Most currently used antibiotics originate from the natural products of actinomycete bacteria, particularly Streptomyces species, that were discovered over 60 years ago. However, genome sequencing has revealed that most antibiotic-producing microorganisms encode many more natural products than previously thought. Biosynthesis of these natural products is tightly regulated by global and cluster situated regulators (CSRs), most of which respond to unknown environmental stimuli, and this likely explains why many biosynthetic gene clusters (BGCs) are not expressed under laboratory conditions. One approach towards novel natural product discovery is to awaken these cryptic BGCs by re-wiring the regulatory control mechanism(s). Most CSRs bind intergenic regions of DNA in their own BGC to control compound biosynthesis, but some CSRs can control the biosynthesis of multiple natural products by binding to several different BGCs. These cross-cluster regulators present an opportunity for natural product discovery, as the expression of multiple BGCs can be affected through the manipulation of a single regulator. This review describes examples of these different mechanisms, including specific examples of cross-cluster regulation, and assesses the impact that this knowledge may have on the discovery of novel natural products.

Screening and Transcriptional Analysis of Polyketide Synthases and Non-ribosomal Peptide Synthetases in Bacterial Strains From Krubera–Voronja Cave

“…Even with a few different test systems used, the compounds cannot be detected if the appropriate PKS and NRPS are not expressed and the compounds are not produced. Production of polyketides and non-ribosomal peptides starts from the transcription of the respective biosynthesis genes (McLean et al, 2019). Therefore, we carried out the transcriptional analysis in order to find if the identified genes are expressed at all, and, if yes, to see if the expression is affected by the amount of the nutrients in the culture medium and/or by the culture growth phase.…”

“…Amos et al (2017) previously reported that in most cases transcription is a good indicator of the compound production. Expression of PKS and NRPS genes is regulated by the complex network of regulators acting as either activators or repressors at the transcription level (van der Heul et al, 2018; Wei et al, 2018; McLean et al, 2019). Despite extensive studies on the global regulator BldA, the only tRNA necessary for the translation of the UUA codons (Hou et al, 2018; van der Heul et al, 2018), little is known about regulation at the pre- and post-transcriptional levels, overall (Wei et al, 2018).…”

Dynamics of the compartmentalizedStreptomyceschromosome during metabolic differentiation

“…formation of the secondary multinucleated mycelium, sporulation) that occurs late in the growth phase. These metabolic and morphological changes are controlled by highly interconnected regulatory mechanisms that have been studied mostly at the transcriptional, translational and post-translational levels [4][5][6][7] . However, a clear link between global chromosome organization and metabolic differentiation has yet to be established.…”

Advances in actinomycete research: an ActinoBase review of 2019

“…For example, the production of actinorhodin in Streptomyces coelicolor is regulated by ActII-4 [19] and CprB [20]. There are also an increasing number of examples of coordinate regulation from one cluster-situated regulator on another BGC [21], such as with FscRI regulating both candicidin and antimycin production in Streptomyces albidoflavus S4 [22]. Lsr2 is a global transcriptional regulator conserved throughout the phylum Actinobacteria that plays an important role in the repression of gene expression.…”