Unlocking the Secrets of an Ancient Antimicrobial, Honey, Using Modern Transcriptomic Techniques

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Antibiotic resistance has been described as an ‘apocalyptic’ threat to human health. As resistance to antibiotics is common soon after they are introduced to clinical use, there is little investment in their development, thus prompting interest in complex natural products as antimicrobials. Honey has been used as a topical wound treatment throughout history, predominantly due to its antimicrobial activity. Manuka honey (from 𝘓𝘦𝘱𝘵𝘰𝘴𝘱𝘦𝘳𝘮𝘶𝘮 𝘴𝘤𝘰𝘱𝘢𝘳𝘪𝘶𝘮 trees) has broad-spectrum antimicrobial activity effective against antibiotic resistant pathogens, such as ciprofloxacin-resistant 𝘗𝘴𝘦𝘶𝘥𝘰𝘮𝘰𝘯𝘢𝘴 𝘢𝘦𝘳𝘶𝘨𝘪𝘯𝘰𝘴𝘢, and is currently approved as a wound treatment. Unlike traditional antibiotics, bacterial resistance to honey has not been reported, however honey remains underutilised in the clinic partly due to a lack of understanding of its mechanism of action. Through passaging experiments, it was found that honey resistance cannot be induced under conditions that rapidly induced resistance to antibiotics. This is due to the complex composition of honey, which is likely to have multiple modes of action, unlike traditional single target antibiotics. The mechanism of action of honey and its key components, methylglyoxal and sugar, was investigated using a transcriptomic approach in a model organism, 𝘗. 𝘢𝘦𝘳𝘶𝘨𝘪𝘯𝘰𝘴𝘢. Results indicate that no single component of honey accounts for its total antimicrobial action and that honey causes DNA and oxidative damage, and affects pathways involved in cell motility, central carbon metabolism, and quorum sensing – explained only partially by its key components. Manuka honey uniquely upregulates genes involved in the explosive cell lysis process, an autolysis mechanism in 𝘗. 𝘢𝘦𝘳𝘶𝘨𝘪𝘯𝘰𝘴𝘢. Honey also downregulates the expression of genes involved in maintaining the electron transport chain and causes protons to leak across biological membranes, ultimately collapsing the proton motive force. Flow cytometry data showed that treatment with manuka honey induces membrane depolarisation and permeabilisation in 𝘗. 𝘢𝘦𝘳𝘶𝘨𝘪𝘯𝘰𝘴𝘢 cells. This was confirmed by modelling membrane potential in liposomes and studying permeabilisation using electrical impedance spectroscopy of tethered lipid bilayer membranes. To investigate whether the membrane damaging action of honey could enhance the action of certain antibiotics, chequerboard assays were used to show that manuka honey acted synergistically with tetracyclines. Taken together, these data argue that manuka honey has multiple mechanisms of action, including the newly described membrane depolarising and permeabilising activity. This thesis contributes to the existing literature demonstrating the potent and unique antimicrobial activity of manuka honey which does not engender bacterial resistance, and supports its inclusion as part of the current array of wound treatments.
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