The Emergence of Honey as an Antimicrobial
A considerable body of historical evidence exists describing the use of honey as a wound treatment as far back as the ancient Egyptians, as well as by field nurses during the world wars.[1] Honey became a neglected treatment following the discovery of penicillin and the antibiotic revolution that subsequently ensued. In 1999 honey was first registered in Australia as a topical medical preparation and since then a range of honey-based products have become available including tubes of sterile manuka honey as well as ointments and honey-impregnated dressings. For the most part, these have remained underused, implemented as a last resort when other treatments have failed. However with the prospect of a return to a purported 'preantibiotic' era in which many antibiotics will become ineffective against bacterial infection, manuka honey could offer an efficacious topical treatment for wounds.
Medical honey preparations can be comprised of various different types of honeys, which depends on the floral source; these are known to include buckwheat, chestnut or clover honeys. However, the only licensed (honey is licensed as a medical device, not a drug), commercially available, sterile (γ-irradiated) medical honey preparations are manuka honey and Revamil™ (floral source unknown).[2] Manuka honey is native to New Zealand and parts of Australia and is produced by bees foraging the manuka bush (Leptospermum scoparium). The very nature of its production means that honey has a complex, often variable chemical composition and it should be noted that not all honeys have equal antimicrobial efficacy. The precise mechanisms by which honeys exert their antimicrobial effects are still incompletely understood; however, it is becoming apparent that these mechanisms are diverse and sometimes specific to particular groups of microorganisms, which will be described in this review.
Chemical Composition of Honeys
Honey production occurs in two stages. First, foraging of nectar by the bee, which invariably leads to the incorporation of hypopharyngeal secretions into the nectar source as it is regurgitated in the hive. Deposited nectar matures in the hive as its moisture evaporates (a process that is facilitated by worker bees) and eventually a viscous, supersaturated sugar solution remains that is the ripened honey. Honeys are comprised primarily of highly concentrated sugars including fructose (~38.2%), glucose (~31.3%) and sucrose (1%), as well as minor components such as acids (0.57%), proteins (0.26%), amino acids (0.1%), nitrogen (0.41%) and minerals (0.17%); the water content is approximately 17% (Table 1).[3] The sugar and water content tends to remain consistent whereas the minor components are highly variable, which gives honeys their diversity. Numerous compounds, in addition to those listed here, form part of this variable fraction and over 600 different constituents have so far been identified, some of which are antimicrobial in nature.
Antibacterial Activity of Honey
It has been long accepted that in part the antimicrobial activity of honeys can be attributed to its high osmolarity (Aw: 0.6) and acidity (pH3.4–6.1), which provide an inhospitable environment for most microorganisms.[4–6] However, artificial honeys that mimic only the sugar component have a lower antimicrobial activity than 'whole' honeys. Proteins are incorporated into honeys in the hive and show considerable variety depending on the bee and plant species from which nectar is derived. These may have direct or indirect antimicrobial functions and examples include glucose oxidase and the antimicrobial peptide, bee defensin.[7] During ripening of the honey, glucose oxidase catalyzes the conversion of glucose to gluconic acid, which results in the production of hydrogen peroxide. For many honeys, the hydrogen peroxide content contributes in a large part to antimicrobial efficacy and can be quenched by the addition of catalase, which leads to a concomitant reduction in antimicrobial activity. Honeys that primarily rely on the production of hydrogen peroxide to mediate their antibacterial effect are described as peroxide honeys. In addition to enzymes, low levels of cationic antimicrobial peptides, such as bee defensin-1, have been identified in some honeys.[7] Bee defensin-1 is produced in the bee salivary gland and is incorporated during primary honey processing. Like other antimicrobial peptides it is a broad-acting protein and is thought to be a constituent of the bee immune system.[8] In manuka honey, bee defensin-1 appears to be modified compared with that found in other honeys, which is thought to be the result of interaction with the phytochemical methylglyoxal (MGO). A second defensin has since been identified (defensin-2), which is believed to act as an inducible antibacterial peptide in bees and may also contribute to the antimicrobial activity of honeys.
Uniquely, manuka honey has very little hydrogen peroxide activity; however, despite this, it has long been regarded as one of the most efficacious honeys known. Numerous studies have since contested this, suggesting that other honeys are as, if not more, effective than manuka honey.[9–12] Studies have revealed that manuka honey contains extremely high concentrations of MGO, which is known to be antimicrobial.[12] Originally identified by HPLC, MGO is found in manuka honey at concentrations of 828 mg/kg compared with 24 mg/kg in non-manuka honeys.[6] It was originally believed that this component was the main 'active' ingredient and has subsequently been referred to as the 'unique manuka factor' (UMF) and is a measure of the antimicrobial activity of manuka honeys.[13] Traditionally the numerical value given to manuka honeys has been measured against a phenol scale as it exhibits a linear correlation with the efficacy of phenol; for example, a manuka honey with a UMF of 18 is therefore, as efficacious as an 18% solution of phenol. Manuka honey for clinical use must have a UMF rating of at least ten to guarantee antimicrobial activity.[6] Despite the potency of MGO, as studies progress, it is becoming apparent that factors other than MGO alone contribute to the antimicrobial activity of manuka honey. Recent nuclear magnetic resonance studies have begun to identify additional 'active' components of manuka honey that exhibit antibacterial properties.[14] So far these have been broadly categorized as either aliphatic or aromatic compounds and members of the latter group were shown to be antibacterial. In particular, this study highlighted the fact that multiple antibacterial compounds are present in manuka honey and that they are likely to be acting synergistically. One such component closely resembled derivatives of inositol at the structural level, which are known to possess antibacterial activity.[14]
Polyphenol & Flavonoid Constituents of Honey
Honeys are known to contain numerous and diverse polyphenolic compounds and flavonoids. The concentration of these is correlated to the color of the honey; generally the darker the honey, the higher the concentration of polyphenols and flavonoids. The floral source impacts greatly upon the type and concentration of polyphenols and flavonoids in honeys and, in addition to color, the concentration of these chemicals also impacts on antimicrobial capacity. For example, Portobello honey and lavender honey both exhibit antimicrobial properties, but to a lesser extent than manuka honey – the reduced antimicrobial function corresponds to a lower concentration of both polyphenols and flavonoids in the honeys compared with manuka honey.[15] Similarly, several Cuban honeys were found to vary considerably in the flavonoid and polyphenol composition; however, in each case, the concentrations corresponded to observed antimicrobial activity with higher antimicrobial activity seen where a higher concentration of polyphenols and flavonoids were present.[16] Flavonoids function as antimicrobials via a diverse set of mechanisms including inhibition of DNA gyrase, cytoplasmic membrane function and energy metabolism, and might be responsible for some of the observed antimicrobial effects of honey as described below.[17,18]
Future Microbiol. 2013;8(11):1419-1429. © 2013 Future Medicine Ltd.
