Exploring the Structure and Activity of Metallo-Tetracyclines

Copper as a key component of electron transport chain of eukaryotes is an essential transition metal ion. Copper homeostasis in mammals complex and tightly regulated. Its strong reactivity together with binding with biologically important chemicals can have important repercussions in human health and overall environment. Tetracycline as one of most abundantly used antibiotic of the world has become abundant in the environment as well. Herein in this dissertation we take the journey to explore the complexation of tetracycline with metals in the environment and the intricate interaction between copper and tetracycline by investigating their oxidative behavior once they are complexed. We further expand the same goal by investigating metalloenzyme mimicking peptide and peptoid interaction with copper and their subsequent activity against catechol oxidation in presence of O2/H2O2 In the first project I explored the tetracycline binding with Calcium by using Ytterbium as a spectroscopic probe through sophisticated paramagnetic Nuclear Magnetic Resonance technique. My study confirms that Calcium can bind to Tetracycline in several different positions and the binding follows a specific order depending on the condition. I also investigated the nature and number of species in solution once tetracycline is complexed with Yb3+. My findings indicate the presence of at least three different species with Yb3+ and 4 different tautomers of the apotetracycline in the complexed solution in d6 -DMSO . In the second project I studied the activities, mechanism and catalytic specificity of the Cu (II) complexes of TTC and O-TTC towards the oxidation of catechol. The investigation revealed the involvement of a dinulear Cu (II) center in the catalysis. We further explored the catechol oxidation under the influence of H2O2 and found out that both the Cu (II) complexes do exhibit specificity towards aerobic oxidation at different extent. The third project covers the activity of copper with tetracycline from an environmental perspective. In this study we investigated the inhibition activities of Salicylic acid, Benzoic acid and Bacitracin; a cyclic peptide antibiotic against Cu (II)-TTC catalyzed oxidation of catechol. Our conclusion based on the experimental data suggests that both salicylic acid and benzoic acid are weak inhibitors toward Cu(II)-TTC-mediated oxidation of catechol, following a mixed inhibition pattern while Bacitracin has a strong inhibition profile with a k ic in the low µM region. All of these inhibitors were picked based on their potential interaction with Cu (II)-Tetracycline and their availability in the environment. My last endeavor into this dissertation covers the activity of synthetic enzymes. I present in this chapter the results about the metal binding capability of a peptide and its oxidation chemistry with and without H2O2 Then we compared the results with those of the Cu (II) complexes of a corresponding peptoid. The study concludes that the peptide binds to Cu (II) as both 1:1, 1:2 metalto-ligand complexes. Both the peptide and peptoid show higher selectivity towards H2O2, with the peptoid showing much higher selectivity compared to peptide