Synthesis, Characterization and Biological Applications of Iron-Based Compounds as New-Generation Antibacterial Drugs

• Main Author: Krishantha Abeydeera, K. G Nalin
• Format: Dissertation
• Language: English
• Published: ProQuest Dissertations & Theses 01-01-2022
• Subjects: Biochemistry; Chemistry
• ISBN: 9798380068314

The rise of antimicrobial resistance (AMR), coupled with the dwindling number of lead compounds in the drug development pipeline, necessitates the search for new antimicrobial agents with modes of action different from those of the conventional antibiotics. To accomplish this goal, I have set out to explore iron compounds as antimicrobial agents in order to access certain modes of action that organic compounds cannot provide. In nature, microorganisms including pathogenic bacteria are faced with two extremely difficult challenges in the acquisition, transport, storage, and utilization of iron. On one hand, the solubility of Fe(III), the stable oxidation state found in the geosphere as oxide minerals is extremely low, rendering direct iron uptake by bacteria impossible to achieve. On the other hand, iron is known to be a double-edged sword inside the cell, i.e., essential for almost all forms of life for survival, division and growth, but potentially toxic to cells if iron homeostasis is disrupted. Cytotoxicity of iron stems from the redox activity of Fe(II) to catalyze the Fenton reaction that produces reactive oxygen species (ROS). As the result, bacteria have acquired sophisticated biochemical systems through evolution to meticulously regulate all aspects of iron metabolism. First, in order to form thermodynamically stable complexes with Fe(III) that is a hard Lewis acid, bacteria manufacture and secrete siderophores - small lipophilic chelating agents consisting of hard-Lewis base O- or N-donor atoms to give rise to high affinity for Fe(III). The resulting soluble Fe(III)-siderophore complexes allow for effective sequestering of Fe(III) in a tight octahedral coordination environment to prevent ligand displacement, trans-metalation and catalytic ROS production. Second, the uptake of a specific Fe(III)-siderophore complex is a tightly regulated receptor-assisted process to ensure excessive iron cannot enter the cell to increase the ion level in the free iron store. Third, once Fe(III)-siderophore complex is transported across the cell membrane, the metal center is reduced to Fe(II) by the enzyme ferric reductase or other intracellular antioxidants to trigger its release because siderophores have relatively low affinity for Fe(II), a soft Lewis acid.Careful examination of such bacterial iron uptake mechanism reveals a vulnerability that may be explored for iron-based antimicrobial drug development. Specifically, if a lipophilic non-siderophore chelating agent with high affinity for Fe(III) but low affinity for Fe(II) is used to transport iron across the cell membrane, the receptor-regulated iron uptake may be circumvented, and Fe(II) would be released via the action of ferric reductase or intracellular antioxidants to increase the iron level in the free iron store, which would trigger the Fenton reaction to produce ROS. The latter can cause oxidative damage to cellular membrane lipids, proteins, enzymes and DNA, leading to cell death. Up to now, iron is generally considered to be a bacterial growth promoter rather than bactericide. As the result, little attempt has been made by the research community to focus on developing iron compounds exclusively as antimicrobial agents. This notion is corroborated by a recent analysis of 906 metal-containing compounds that have been screened for antimicrobial activity by the Community for Open Antimicrobial Drug Discovery (CO-ADD). The report of such analysis has identified a score of antimicrobial metals including Mn, Co, Zn, Ru, Ag, Eu, Ir and Pt whose complexes have produced hits in the category of “active and nontoxic” lead compounds against at least one pathogenic organism, but Fe is noticeably missing from this list. Therefore, I have begun to explore the capability of neutral octahedral Fe(III)-complexes formed with various bidentate chelating ligands containing the hard Lewis donor atoms of O and/or N to disrupt the regulation of iron uptake in bacteria, and thus delivering iron across the cell membrane for the benefit of developing iron-based antimicrobial agents. The rationale behind this approach is that the formation of such Fe(III)-complexes with D3 symmetry would cause the molecular polarity to vanish as well as conceal the ionic character of the metal center inside the octahedral pocket, rending the complexes greaseball-like feature to facilitate the transport of the complexes across the cell membrane. Thus far, among various chelating ligands (i.e., acetylacetone, 2,2-bipyridine, deferiprone, ethyl maltolate, hinokitiol, methyl maltolate and 1,10 phenanthroline, etc.), I have examined for such purposes.