Scientists from the Department of Chemistry, Tomislav Jednačak, Branimir Bertoša, and Predrag Novak, along with former doctoral students Ivana Mikulandra and Andrea Hloušek-Kasun, and postdoctoral researcher Kristina Smokrović, as well as students Monika Kapustić and Kristina Delaš, in collaboration with scientists Ivo Piantanida and Marta Jurković from the Ruđer Bošković Institute and Professor Klaus Zangger from the University of Graz, published a scientific paper titled Antimicrobial macrozones interact with biological macromolecules via two-site binding mode of action: Fluorimetric, NMR and docking studies u prestižnom časopisu Bioorganic Chemistry (Q1, IF = 5,1).
A combination of spectrometric (fluorimetry, STD and WaterLOGSY NMR) and molecular docking studies provided insights into atomic details of interactions between selected macrozones and biological receptors such as E. coli ribosome and bovine serum albumin. Fluorimetric measurements revealed binding constants in the micro-molar range while NMR experiments provided data on binding epitopes. It has been demonstrated that both STD and WaterLOGSY gave comparable and consistent results unveiling atoms in intimate contacts with biological receptors. Docking studies pointed towards main interactions between macrozones and E. coli ribosome which included specific π - π stacking and hydrogen bonding interactions with thiosemicarbazone part extending down the ribosome exit tunnel. The results of the docking experiments were in fine correlation with those obtained by NMR and fluorimetryOur investigation pointed towards a two-site binding mechanism of interactions between macrozones and E. coli ribosome which is the most probable reason for their activity against azithromycin-resistant strains. Much better activity of macrozone-nickel coordinated compound against E. coli ribosome compared to other macrozones has been attributed to the higher polarity which enabled better bacterial membrane penetration and binding of the two thiosemicarbazone units thus additionally contributing to the overall binding energy. The knowledge gained in this study should play an important role in anti-infective macrolide design in the future.
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