The increasing antibiotic resistance among bacterial pathogens means that the therapeutics currently used against infectious diseases are ineffective. Using a combinatorial biosynthesis approach and additional chemical modifications, we have developed a novel chimeric antibiotic called clincelin, whose core structurally combines two naturally occurring lincosamide antibiotics, celesticetin and lincomycin (1). Our extensive in vivo activity testing shows that clincelin has significantly higher antibacterial activity compared to the original natural compounds and that it retains antibacterial activity even against resistant strains, including strains expressing the highly efficient ribosomal methyltransferase Erm. Subsequent cryo-EM structural analysis revealed that the drug can bind to a staphylococcal ribosome in two different binding modes to overcome this resistance mechanism. Our data contribute to the further development of novel lincosamide antibiotics aiming for introduction to clinical use.
1. Kadlčík,S., Kameník,Z., Vašek,D., Nedvěd,M. and Janata,J. (2017) Elucidation of salicylate attachment in celesticetin biosynthesis opens the door to create a library of more efficient hybrid lincosamide antibiotics. Chem Sci, 8, 3349–3355.