Underground Storage and the Pressure to Defend It

My previous article notes that bees evolved from wasps and originally nested underground, a detail worth dwelling on, because it is central to why bioactivity exists at all. Soil is one of the densest microbial environments on Earth, packed with bacteria, fungi, and moulds constantly probing for organic matter to colonise. Any creature that stores a concentrated, sugar-rich food supply in that environment is storing an irresistible target. A cache of nectar or honey left undefended underground would be overrun by soil pathogens within days.

This is the evolutionary pressure that made bioactive honey inevitable rather than incidental. Any lineage of bees that stored food underground and failed to evolve a chemical defence against spoilage and infection simply would not have survived to pass on that behaviour. Over hundreds of millions of years, this pressure selected for bees that could lace their stored food with antimicrobial compounds potent enough to hold off an entire soil microbiome, not just the odd airborne bacterium. Honey’s antibacterial strength, in other words, is not a lucky side effect of nectar chemistry; it is a load-bearing survival trait, refined against one of the most hostile microbial environments a food source can be kept in.

Enter Apis mellifera

Of the roughly ten recognised species in the genus Apis, only two have ever been domesticated for honey production at scale: Apis cerana in India, and Apis mellifera, the western honey bee. Genomic studies now point to a northern African or Middle Eastern origin for the species, from where it spread into Europe, western Asia, and sub-Saharan Africa long before humans began managing it. Unlike Australia’s stingless bees, Apis mellifera builds large, vertically-stacked wax combs and can sustain colonies of tens of thousands of workers, the biological basis for the honey volumes beekeeping depends on today.

Its relationship with humans is old. Beekeeping is documented in Egypt as far back as 2600 BCE, and by the time colonists carried “dark bees” to Jamestown in 1622, the species had already been managed by humans for millennia. That long history of selective management is why Apis mellifera (rather than any of its wild relatives) became the species capable of producing honey in the quantities needed for commercial and medicinal use.

Leptospermum and the Chemistry of Bioactivity

The original article named Tea Tree (genus Leptospermum) as a key contributor to bioactivity, and it’s worth explaining why. Most honey owes its mild antibacterial action to hydrogen peroxide, generated when the bee enzyme glucose oxidase reacts with nectar sugars. But honey made from Leptospermum nectar (manuka in New Zealand, and several related species across Australia) carries an additional and far more potent weapon: methylglyoxal, or MGO.

MGO forms from dihydroxyacetone (DHA), a compound that accumulates in unusually high concentrations in Leptospermum nectar and slowly converts to MGO as the honey matures. Unlike hydrogen peroxide, MGO is not neutralised by catalase enzymes present in human blood and tissue, which is what makes it clinically useful. It keeps working at the wound site. MGO kills bacteria by binding to proteins on the microbial cell surface through a process called glycation, disabling them, and it separately disrupts flagellation and cell division. The concentration of MGO in a given honey correlates directly with its measured antibacterial strength, which is the basis of the Unique Manuka Factor (UMF) grading system used commercially.

This lines up directly with the article’s closing point about resistance: because MGO attacks bacteria through several physical and chemical mechanisms at once, rather than targeting one specific protein the way most pharmaceutical antibiotics do, laboratory studies have not been able to induce bacterial resistance to it, mirroring honey’s much older evolutionary track record against pathogens.

From Hive to Hospital: Medical-Grade Honey

This chemistry has moved well beyond folk remedy. Medical-grade Leptospermum honey, sterilised, standardised, and rated by MGO content, is now a registered wound-care product in Australia, New Zealand, Canada, the European Union, Hong Kong, and the United States. In controlled studies it has shown effectiveness against a wide range of wound pathogens, including antibiotic-resistant strains such as MRSA, and it has demonstrated anti-biofilm activity that plain antiseptics often lack.

In a porcine burn-wound model comparing manuka-honey dressings to standard care, honey-treated wounds showed a 54% re-epithelialisation rate by day seven versus 31% for the control group, and by day ten that gap had widened to 85% versus 72%, with the manuka-treated wounds eventually achieving complete healing and thicker new tissue at every stage measured.

This is arguably the frontier the article’s evolutionary story has been building toward: several hundred million years of bee-microbe warfare, distilled into a jar, and now being put to direct clinical use in modern wound care.

References

Tihelka, E., Cai, C., Pisani, D., & Donoghue, P. C. J. (2020). Mitochondrial genomes illuminate the evolutionary history of the Western honey bee (Apis mellifera). Scientific Reports, 10, 14515. https://doi.org/10.1038/s41598-020-71393-0

Cridland, J. M., Tsutsui, N. D., & Ramírez, S. R. (2017). The complex demographic history and evolutionary origin of the western honey bee, Apis mellifera. Genome Biology and Evolution, 9(2), 457–472. https://doi.org/10.1093/gbe/evx009

Requier, F., et al. (2023). Multiple mitogenomes indicate “Things Fall Apart” with Out-of-Africa or Out-of-Asia hypotheses for the phylogeographic evolution of honey bees (Apis mellifera). Scientific Reports, 13, 9386.

Rangel, J., & Giresi, M. (2021). Genetic past, present, and future of the honey bee (Apis mellifera) in the United States of America. Apidologie, 52, 1140–1157.

Kwakman, P. H. S., et al. (2010). How honey kills bacteria. The FASEB Journal, 24(7), 2576–2582.

Mavric, E., Wittmann, S., Barth, G., & Henle, T. (2008). Identification and quantification of methylglyoxal as the dominant antibacterial constituent of manuka (Leptospermum scoparium) honeys from New Zealand. Molecular Nutrition & Food Research, 52(4), 483–489.

Girma, A., Seo, W., & She, R. C. (2019). Antibacterial activity of varying UMF-graded manuka honeys. PLOS ONE / PMC6814216.

Alhabsi, K., et al. (2026). Clinical and postoperative applications of manuka honey in wound healing: An evidence-based review. International Wound Journal. https://doi.org/10.1111/iwj.70939

Barazesh, A., et al. (2025). Unlocking the healing potential: A comprehensive review of ecology and biology of medical-grade honey in wound management and tissue regeneration. Health Science Reports, 8(1). https://doi.org/10.1002/hsr2.70240

Girma, A., et al. (2020). The antibacterial activity of Australian Leptospermum honey correlates with methylglyoxal levels. Complementary Therapies in Medicine / PMC5193333.

George, N. M., & Cutting, K. F. (2007). Antibacterial honey (Medihoney™): In-vitro activity against clinical isolates of MRSA, VRE, and other multiresistant Gram-negative organisms including Pseudomonas aeruginosa. Wounds, 19(9), 231–236.

Molan, P. C., & Rhodes, T. (2015). Honey: A biologic wound dressing. Wounds, 27(6), 141–151.

Halstead, F. D., et al. (2016). The efficacy of honey as a wound dressing: An updated review. Wound Practice and Research, 24(2), 76–85.

Weber, E. (2012). Apis mellifera: The domestication and spread of European honey bees for agriculture in North America. University of Michigan Undergraduate Research Journal, 9.