While natural products derived from Streptomyces species were once thought to be exhausted, advances in bioinformatic tools and genome sequencing have revealed that BGCs are far more abundant than previously thought, averaging 39 per genome ( 6). BGCs typically consist of dozens of genes that are co-localized at a single portion of a bacterial genome and encode components for natural product synthesis, transport, regulation, and resistance ( 6). Microbial natural products are encoded by complex genomic regions called Biosynthetic Gene Clusters (BGCs). Natural products derived from Streptomyces species are a likely major source of new antibiotics ( 5). However, over the last decades, there has been a sharp decline in the discovery of new antibiotics, and it is widely recognized that innovative approaches for antibiotic discovery are required ( 4). Addressing the antibiotic resistance crisis requires a multipronged approach, including the discovery of new antibiotics for which resistance has not been reported ( 3). Together, this work advances the synthetic regulatory toolbox for Streptomyces and facilitates the programmable activation of silent BGCs for novel chemical discovery.īacterial resistance to antimicrobial agents is globally recognized as one of the major challenges facing public health ( 1, 2). We then harness these tools to activate a silent BGC by perturbing its endogenous regulatory network. First, we refine CRISPR interference (CRISPRi) and create CRISPR activation (CRISPRa) systems that allow for highly programmable and effective gene repression and activation in Streptomyces. To address this, we describe a novel approach to activate silent BGCs through rewiring endogenous regulation using synthetic gene regulators based upon CRISPR-Cas. However, a major challenge is that the biosynthetic gene clusters (BGCs) responsible for natural product synthesis are often poorly expressed under laboratory culturing conditions, thus preventing the isolation and screening of novel chemicals. Natural products derived from the genus Streptomyces represent a rich and diverse repertoire of chemical molecules from which new antibiotics are likely to be found. The rise of antibiotic-resistant bacteria represents a major threat to global health, creating an urgent need to discover new antibiotics.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |