Towards new more efficient and clinically relevant lincosamide antibiotics Zdenek Kamenik and Radek Gazak Institute of Microbiology Czech Acad Sci, Czech Republic Lincosamides are a small group of clinically used antibiotics of microbial origin with a relatively simple structure, but remarkably complex biosynthesis. The most efficient lincosamide is semisynthetic clindamycin, which is also used to treat malaria. We have combined biosynthetic pathways of two natural lincosamides using a mutasynthetic in vivo/in vitro approach and came up with a hybrid lincosamide, CELIN, which surpasses the bioactivity of clindamycin against several pathogens of concern, including Staphylococcus aureus and Clostridioides (Clostridium) difficile . To scale up the preparation of our most potent CELIN derivative, we used commercially available lincomycin and converted its thiomethyl group into a thiohydroxyethyl group, to which an organic acid was attached. While this CELIN derivative is currently in preclinical trials, we pursuit to increase the antibiotic activity even further by additional chemical synthesis. Specifically, we stereoselectively convert L-pyroglutamic acid to 4-pentyl-L-proline in six steps and condense it with an unusual ominooctose (thiolincosaminide), leading to the lincosamide scaffold with a long alkyl side chain, which increases the antibiotic activity. The lecture will focus on our most recent yet unpublished data and will put it into the context with synthetic lincosamides, overcoming bacterial resistance, recently published in Nature by the Meyers group 1 . References 1. Matthew J. Mitcheltree, Amarnath Pisipati, Egor A. Syroegin, Katherine J. Silvestre, Dorota Klepacki, Jeremy D. Mason, Daniel W. Terwilliger, Giambattista Testolin, Aditya R. Pote, Kelvin J. Y. Wu, Richard Porter Ladley, Kelly Chatman, Alexander S. Mankin, Yury S. Polikanov& Andrew G. Myers:A synthetic antibiotic class overcoming bacterial multidrug resistance, 2021, 599, 507-512.
C07
© The Author(s), 2022
Made with FlippingBook Learn more on our blog