#ancientbiotics

“Bald’s eyesalve. A facsimile of the recipe, taken from the manuscript known as Bald’s Leechbook (London, British Library, Royal 12, D xvii). The original text reads as follows. “Ƿyrc eaȝsealf ƿiþ ƿænne: ȝenim cropleac ⁊ ȝarleac beȝea emfela, ȝecnuƿe ƿel tosomne, ȝenim ƿin ⁊ fearres ȝeallen beȝean emfela ȝemenȝ ƿiþ þy leaces, do þonne on arfæt læt standan niȝon niht on þæm arfæt aƿrinȝ þurh claþ ⁊ hlyttre ƿel, do on horn ⁊ ymb niht do mid feþre on eaȝe; se betsta læcedom.” This is translated into modern English as follows. “Make an eyesalve against a wen: take equal amounts of cropleac [an Allium species] and garlic, pound well together, take equal amounts of wine and oxgall, mix with the alliums, put this in a brass vessel, let [the mixture] stand for nine nights in the brass vessel, wring through a cloth and clarify well, put in a horn and at night apply to the eye with a feather; the best medicine.” - The British Library Board, Royal 12 D Xll xvii.”

ABSTRACT

Plant-derived compounds and other natural substances are a rich potential source of compounds that kill or attenuate pathogens that are resistant to current antibiotics. Medieval societies used a range of these natural substances to treat conditions clearly recognizable to the modern eye as microbial infections, and there has been much debate over the likely efficacy of these treatments. Our interdisciplinary team, comprising researchers from both sciences and humanities, identified and reconstructed a potential remedy for Staphylococcus aureus infection from a 10th century Anglo-Saxon leechbook. The remedy repeatedly killed established S. aureus biofilms in an in vitro model of soft tissue infection and killed methicillin-resistant S. aureus (MRSA) in a mouse chronic wound model. While the remedy contained several ingredients that are individually known to have some antibacterial activity, full efficacy required the combined action of several ingredients, highlighting the scholarship of premodern doctors and the potential of ancient texts as a source of new antimicrobial agents.

IMPORTANCE While the antibiotic potential of some materials used in historical medicine has been demonstrated, empirical tests of entire remedies are scarce. This is an important omission, because the efficacy of “ancientbiotics” could rely on the combined activity of their various ingredients. This would lead us to underestimate their efficacy and, by extension, the scholarship of premodern doctors. It could also help us to understand why some natural compounds that show antibacterial promise in the laboratory fail to yield positive results in clinical trials. We have reconstructed a 1,000-year-old remedy which kills the bacteria it was designed to treat and have shown that this activity relies on the combined activity of several antimicrobial ingredients. Our results highlight (i) the scholarship and rational methodology of premodern medical professionals and (ii) the untapped potential of premodern remedies for yielding novel therapeutics at a time when new antibiotics are desperately needed.

Bald’s Leechbook (7) (Materials and Methods) is an English medical text from the Anglo-Saxon period. The manuscript was written in the 10th century and contains remedies for various ailments, including clearly recognizable microbial infections. Medieval medicine has generally been dismissed as backwards or superstitious, but recent scholars have suggested that among the remedies there may be methods and recipes that indicate a more factual application (8–10). One of Bald’s remedies, a salve for a “wen” or lump in the eye (Fig. 1), is particularly interesting to the modern microbiologist. It aims to treat a condition caused by bacterial infection and contains ingredients with the potential for antimicrobial activity. The recipe instructs the reader to crush garlic and a second Allium species (whose translation into modern English is ambiguous), combine these with wine and oxgall (bovine bile), and leave the mixture to stand in a brass or bronze vessel for 9 days and nights.

DISCUSSION

In summary, we have reconstituted a 1,000-year-old remedy for bacterial infection and shown that it kills the most common cause of the infection it was designed to treat. Bald’s eyesalve eliminates S. aureus in planktonic culture and reduces viable cell numbers by several orders of magnitude in a synthetic model of established biofilm infection. This effect depends upon the combination of several ingredients and upon the 9-day storage period specified in the recipe. Furthermore, a highly antibiotic-resistant strain of S. aureus is susceptible to Bald’s eyesalve when infected tissue from a mouse chronic wound model is exposed to the recipe. In this model, significant bactericidal activity was observed after a brief period of exposure during which the current last-line clinical antibiotic (vancomycin) did not kill significant numbers of bacteria. Our findings contrast with those of a previous attempt to test Bald’s eyesalve by Brennessel et al. (23), who found it ineffective against S. aureus in disk diffusion assays; however, these authors do not specify the methods of preparation and do not give quantitative results or details of replication, so we do not know exactly how their tests were conducted.

Future work will explore the mechanism(s) by which Bald’s eyesalve kills S. aureus. We note that several of the ingredients may damage biological membranes. Bile salts act as surfactants (15), the Ace-AMP1 antimicrobial peptide present in onion is thought to have lipid-binding activity (19), and saponins, present in a wide variety of Allium spp., can bind the sterols present in biological membranes (3). Other antimicrobial compounds present in Allium spp. have been shown to act as enzyme inhibitors (allicin and flavonoids) (3). Wine may be a source of further plant-derived antimicrobial small molecules, or it may simply act as a solvent for the extraction of compounds from the other ingredients in the recipe, with the 9-day waiting period providing time for molecule extraction.

It is interesting that copper was entirely dispensable for antistaphylococcal activity in our synthetic wound model. Copper has been shown to have broad-spectrum antibacterial activity (16, 17), and we would expect copper salts to accumulate in our preparations: we observed copper compounds forming on the surface of the brass squares used to simulate the preparation vessel, and Brennessel et al. (who used an actual brass pot), found that copper salts accumulated to high levels in their version of Bald’s eyesalve (M. Drout, personal communication). It is possible that we simply did not have a large enough copper surface to allow copper to accumulate to biologically active levels in our recipe. Alternatively, the copper vessel itself may have allowed the Anglo-Saxon physician to begin work with an uncontaminated pot due to the resistance of copper surfaces to bacterial colonization. A third possibility is that copper is entirely dispensable: copper alloy bowls of the Anglo-Saxon period can be highly decorated (even inlaid with silver) and appear as grave goods in high status burials as a marker of feasting power (24), and perhaps the more humble vessels may have been a marker of the physician’s professional status.

The combined activity of molecules derived from the different ingredients might explain why the activity of Bald’s eyesalve is greater than the sum of its parts: the mixture may attack the bacteria on several fronts. This is an important consideration for future work on natural antimicrobial compounds, as strong in vitro activity of individual compounds has not always translated into positive in vivo results (6). Alternatively, novel compounds may be formed as molecules from different ingredients react over the 9-day storage period specified by the recipe. Future research into antibiotics derived from natural materials would benefit from considering potential combinatorial activity of different ingredients, and premodern medical texts provide an excellent starting point for this strategy. Such work will require extensive collaborative research involving historians, linguists, microbiologists, and analytical/medicinal chemists.

When we describe Bald’s eyesalve as being “designed” to treat eye infection, we do not use the term lightly. There has been considerable debate about the levels of scholarship and scientific method among early medieval medical practitioners (8, 9, 25). This may be partly because of an almost complete absence of theoretical material, and the fact that the surviving corpus of Anglo-Saxon medicine seems to be compilations of excerpts and treatises (26). Furthermore, many recipes—such as the one that requires having a virgin get water from an eastward-flowing spring for a cyst “which pains the heart,” from the mid-11th century Lacnunga—look rather dubious as remedies. Medicine, as some scholars have claimed, was a craft and not a science in early medieval Europe (26), and there was a lack of explanatory frameworks. Texts like Bald’s Leechbook were most likely composed in a monastic environment, and in many text sources, there is a conflation of spiritual and practical healing. More credence has been given to later medieval texts, associated with the School of Salerno and the growth of university-based training (27).

ABSTRACT: Plant-derived compounds and other natural substances are a rich potential source of compounds that kill or attenuate pathogens that are resistant to current antibiotics. Medieval societies used a range of these natural substances to treat conditions clearly recognizable to the modern eye as microbial infections, and there has been much debate over the likely efficacy of these treatments. Our interdisciplinary team, comprising researchers from both sciences and humanities, identified and reconstructed a potential remedy for Staphylococcus aureus infection from a 10th century Anglo-Saxon leechbook. The remedy repeatedly killed established S. aureus biofilms in an in vitro model of soft tissue infection and killed methicillin-resistant S. aureus (MRSA) in a mouse chronic wound model. While the remedy contained several ingredients that are individually known to have some antibacterial activity, full efficacy required the combined action of several ingredients, highlighting the scholarship of premodern doctors and the potential of ancient texts as a source of new antimicrobial agents. 

Ancient Potion Kills 99.99% of MRSA Bacteria

Could a 1,000-year-old concoction be the answer to stopping superbugs? Christina Lee, an Anglo-Saxon expert at the University of Nottingham, found the recipe for a remedy for eye infections in a 10th Century medical volume called Bald’s Leechbook, one of the earliest known medical textbooks. The instructions were clear — clear enough to follow today — so she brought it to a microbiology lab at…