College of Science and Health Theses and Dissertations

Date of Award

Fall 11-20-2012

Degree Type

Thesis

Degree Name

Master of Science (MS)

Department

Chemistry

First Advisor

Lihua Jin, PhD

Second Advisor

Caitlin Karver, PhD

Third Advisor

Quinetta Shelby, PhD

Abstract

Tetracyclines are a group of antibiotics that are known to bind physiologically relevant metal ions, such as Ca2+, for antibacterial activity. The formation of the[ antibiotic-Ca2+l complex can interact with components in the gastrointestinal tract, including the bile salts, and reduce their absorption into the blood plasma after oral administration. Metal ion interactions between Ca2+ and tetracycline have been the focus of numerous studies while interactions with minocyclinc and tigccyclinc have been scarcely explored. Isothermal titration calorimetry (ITC) was employed to study the interaction of three members of the tetracycline family, tetracycline (TtC), minocyclinc (MC), and tigecycline (TgC), with Ca2+and taurocholate (TC), which is a bile acid. The energetics associated with Ca2coordination to each antibiotic in N-cthylmorpholinc (NEM) and tris(hydroxymethyl)aminomethane (Tris) buffer at pH 6.8 and 7.5, the influence of ionic strength (6mM- 0.15 M NaCl) on Ca2+ and taurocholate binding, and the affinity of taurocholate to the [ antibiotic-Ca 2+l complex were examined. The relative binding stoichiometry (n) and affinity (KJ for Ca2 were found to correlate with the chemical structure of the antibiotics. Taurocholate affinity of the [antibiotic-Ca 2+l complex was found to correlate with the relative bioavailability of the antibiotics. This study provides information that can serve useful for designing tetracycline family antibiotics with improved metal ion affinity for increased oral bioavailability and thus improved absorption.

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