Discovery of a Potent Adenine–Benzyltriazolo–Pleuromutilin Conjugate with Pronounced Antibacterial Activity against MRSA
Christoffer V. Heidtmann, Faidra Voukia, Louise N. Hansen, Stine H. Sørensen, Brian Urlund, Salli Nielsen, Mona Pedersen, Noor Kelawi, Brian N. Andersen, Maria Pedersen, Peter Reinholdt, Jacob Kongsted, Carsten Uhd Nielsen, Janne Kudsk Klitgaard, Poul Nielsen
Abstract
Conjugation of pleuromutilin is an attractive strategy for the development of novel antibiotics and the fight against multiresistant bacteria as the class is associated with low rates of resistance and cross-resistance development. Herein, the preparation of 35 novel (+)-pleuromutilin conjugates is reported. Their design was based on a synthetically more efficient benzyl adaption of a potent lead but still relied on the Cu(I)-catalyzed alkyne–azide [3 + 2] cycloaddition for conjugation onto pleuromutilin. Their antibacterial activity was evaluated against the multiresistant Staphylococcus aureus strain USA300 for which they displayed moderate to excellent activity. Compound 35, bearing a para-benzyladenine substituent, proved particularly potent against USA300 and additional strains of MRSA and displayed as importantly no cytotoxicity in four mammalian cell lines. Structure–activity relationship analysis revealed that the purine 6-amino is essential for high potency, likely because of strong hydrogen bonding with the RNA backbone of C2469, as suggested by a molecular model based on the MM-GBSA approach.