Abstract
Daptomycin, which is produced by Streptomyces roseosporus, has been characterized as a novel cyclic lipopeptide antibiotic that is effective against Gram-positive bacteria. The biosynthesis of daptomycin is regulated by various factors. In the present study, we demonstrated that the cyclic AMP receptor protein (Crp) plays an important role in producing daptomycin in the S. roseosporus industrial strain. We found that daptomycin production from the crp deletion strain decreased drastically, whereas production from the crp overexpression strain increased by 22.1%. Transcriptome and qPCR analyses showed that some genes related to the daptomycin biosynthetic gene cluster (dpt) and the pleiotropic regulator (adpA) were significantly upregulated. RNA-seq also shows Crp to be a multifunctional regulator that modulates primary metabolism and enhances precursor flux to secondary metabolite biosynthesis. These results provide guidance for the development and improvement of potential natural products.
Highlights
Cyclic lipopeptides (CLPs) are antibiotics widely used for the treatment of infections by Grampositive organisms (Gotze et al, 2017), such as rapidly emerging antibiotic-resistant bacteria
Cyclic AMP receptor protein is broadly distributed in a variety of bacteria and regulates multiple biological activities, such as glucose starvation, cell differentiation, and primary metabolism (Shimada et al, 2011)
Analysis of the transcriptome data of SR1101 and SR1130 shows that Crp acted in two ways (Figure 5): (I) Crp regulated the expressions of some dpt genes during daptomycin production
Summary
Cyclic lipopeptides (CLPs) are antibiotics widely used for the treatment of infections by Grampositive organisms (Gotze et al, 2017), such as rapidly emerging antibiotic-resistant bacteria. Daptomycin is a CLP that is produced by Streptomyces roseosporus through a non-ribosomal peptide synthetase (NRPS) pathway. This CLP is classified as a last-resort antibiotic, along with vancomycin and linezolid (Gray and Wenzel, 2020), which was first reported by Eli Lilly and Company (Kirkpatrick et al, 2003) and was approved by the FDA in 2003 to treat skin infections and bacteremia caused by Gram-positive bacteria, especially methicillin-resistant Staphylococcus aureus (MRSA) (Nguyen et al, 2006). The daptomycin biosynthesis pathway is initiated by the activation of decanoic acid by DptE (an acyl-CoA ligase). The acid is transferred onto an acyl carrier protein (encoded by dptF) and coupled with the N-terminus of the tyrosinase related protein (Trp1) as a fatty acid
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