The following discussion of the background of the invention is merely provided to aid the reader in understanding the invention and is not admitted to describe or constitute prior art to the present invention.
A search for alternatives to traditional antibiotics has led to the exploitation of reactive oxygen species for purposes of antimicrobial therapies. For example, photodynamic therapy, in which a photosensitizer such as methylene blue is targeted to a microorganism, followed by illumination with light to generate reactive oxygen species, has been shown to be effective against a broad spectrum of pathogens. Additionally, metals such as iron, copper, chromium, vanadium and cobalt are capable of redox cycling in which a single electron may be accepted or donated by the metal. This action catalyzes reactions that produce reactive radicals and can produce reactive oxygen species. For example, hydroxyl radical production by catalytic metal complexes can lead to modifications of amino acids (e.g. meta-tyrosine and ortho-tyrosine formation from phenylalanine), carbohydrates, initiate lipid peroxidation, and oxidize nucleobases. Metallodrugs, which typically comprise a metal binding moiety in a complex with a targeting moiety, take advantage of this redox cycling to generate reactive oxygen species. Not surprisingly, such metallodrugs have also been investigated for their antimicrobial capabilities. The development of such metallodrugs as therapeutic agents, however, has typically focused on the use of the targeting moiety to position the catalytic metal into close proximity with a target nucleic acid or protein, so as to take advantage of cleavage or modification of a specific target molecule.
“Oxidative stress” refers to toxic effects mediated by the production of peroxides and free radicals, causing non-specific damage to various components of the cell, including proteins, lipids, and DNA. Moreover, because reactive oxidative species can act as cellular messengers through a phenomenon called redox signaling, disturbances in the normal redox state of tissues can cause alterations both in conformation and activity of a number of enzymes. Phosphotyrosine phosphatases (PTPs) serve as important regulators of cellular signal transduction pathways. PTPs are sensitive targets of oxidative stress and may be inhibited by treatments that induce intracellular oxidation. The effects of PTP inactivation under oxidizing conditions are amplified by the redox-linked activation of key protein tyrosine kinases (PTKs), thus leading to the initiation of phosphotyrosine-signaling cascades that are no longer under normal receptor control.
An imbalance between the production of reactive oxygen species and a biological system's ability to readily remove such species or to repair the resulting damage can cause cell death; even moderate oxidation can trigger apoptosis, while more intense stresses may cause necrosis. The mammalian immune system takes advantage the lethal effects of oxidants by making production of oxidizing species a central part of its mechanism of killing pathogens; with activated phagocytes producing both ROS and reactive nitrogen species. These include superoxide (.O2-), nitric oxide (.NO) and their particularly reactive product, peroxynitrite (ONOO—). While the non-specificity of oxidative stress can prevent a pathogen from becoming resistant through mutation of a single molecular target, non-specific use of these highly reactive compounds in response to pathogens results in significant damage to host tissues.