Relieving glucose-mediated carbon catabolite repression to engineer antibiotic over production in Streptomyces species
Streptomyces is the largest genus of bacteria, well studied because it makes molecules called specialised metabolites that form the basis of 55% of antibiotics as well as other anti-infective, anti-cancer and immunosuppressant drugs. Almost all these molecules were discovered >60 years ago, and their widespread use has led to pathogenic bacteria becoming resistant to many clinically used antibiotics. This continued evolution of antimicrobial resistance (AMR) in bacteria represents a significant threat to global health and means that new antibiotics with novel mechanisms of action are urgently needed.
Antibiotic discovery is currently hampered by the fact that antibiotic biosynthesis is inhibited by glucose. This limits the kind of growth media that can be used to culture Streptomyces bacteria and thus limits the chances of discovering new molecules. However, we recently discovered that removing a signalling system called CutRS makes Streptomyces species overproduce antibiotics in the presence of glucose. This will be valuable to industry, because when we delete the cutRS genes the bacteria grow faster and overproduce antibiotics in glucose-containing growth media. It will also be useful for the discovery of new antibiotics because it means we can grow the bacteria on any growth media.
This project aims to understand why loss of CutRS makes Streptomyces bacteria over-produce antibiotics in the presence (but not absence) of glucose. You will test this in the model species Streptomyces venezuelae, by investigating all genes controlled directly or indirectly by CutR. You will also test whether removing CutRS works in industrially important antibiotic-producing strains, i.e., can you make these strains over produce valuable antibiotics in the presence of glucose which would be very attractive to the pharmaceutical industry. Finally, you will test whether any new molecules are produced by the mutant strains you make in this study.
References
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Romero-Rodríguez A, Rocha D, Ruiz-Villafán B, Guzmán-Trampe S, Maldonado-Carmona N, Vázquez-Hernández M, Zelarayán A, Rodríguez-Sanoja R, Sánchez S. Carbon catabolite regulation in Streptomyces: new insights and lessons learned. World J Microbiol Biotechnol. 2017 Sep;33(9):162. doi: 10.1007/s11274-017-2328-0. Epub 2017 Aug 2. PMID: 28770367.
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