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Title: Carbon monoxide and carbon monoxide-releasing molecules as novel antibacterial agents : mechanisms of toxicity and resistance
Author: Jesse, Helen
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2012
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Carbon monoxide (CO) is commonly considered to be toxic due to the propensity of this gaseous molecule to bind to ferrous iron in haemoglobin and cytochromes, thereby inhibiting respiration and the transport of oxygen around the body. However, CO is produced endogenously by haem oxygenases and has various cytoprotective functions including being vasodilatory, anti-inflammatory and anti-apoptotic. The development of CO-RMs (Carbon Monoxide-Releasing Molecules), which are generally transition metal carbonyls that release CO under certain conditions, has facilitated research into the physiological effects of CO and the potential use of CO as a therapeutic agent. Furthermore, CO-RMs have been found to reduce significantly the viability of various Gram-positive and Gram-negative bacteria, which is thought to be caused in part by the binding of CO from CO-RMs to the terminal oxidases of aerobic respiratory chains. Interestingly, CO-RMs are known to elicit many effects distinct from those of CO gas, including acting as more potent bactericidal agents. This thesis aims to increase the current knowledge of the antibacterial effects of CORMs, with a particular focus on the interactions with respiration, oxidases and thiol compounds. In contrast to CO gas, CORM-3 was not preferentially inhibitory to respiration at low oxygen tensions; however, in accordance with the relative resistance of cytochrome bd-I to CO gas, this oxidase was found to be the most resistant of E. coli to respiratory inhibition by CORM-3, and possession of this oxidase conferred some protection against growth inhibition in the presence of this CO-RM. Inhibition of E. coli respiration by CORM-3 was photosensitive and light reduced significantly the toxic effects of this compound, suggesting that CO from CORM-3 binds to ferrous haems in a classical, light-sensitive manner. This supports the hypothesis that the binding of CO from CORM-3 to haemoproteins is largely responsible for killing by these compounds. However, in opposition to this hypothesis, the non-haem oxidase AOX from Vibrio fischeri was found to be hypersensitive to inhibition by CORM-3, but not to CO, emphasising the complex effects of these compounds. Data are presented to show that thiol-containing compounds, which have been widely reported to abolish the biological effects of CO-RMs, substantially reduce the uptake of ruthenium-containing CO-RMs. The generation of reactive oxygen species by CO-RMs is also demonstrated and investigated. Finally, the generation and preliminary characterisation of CO-RM-resistant E. coli mutants is described. This work was done with the aim of revealing previously unappreciated bacterial targets for CO-RMs. Sugar-transporting phosphotransferase systems were identified as a possible means of CO-RM entry into the bacterial cell.
Supervisor: Poole, R. K. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available