Biology subjects

Furner-Pardoe, J.

Publications and source records attributed to Furner-Pardoe, J..

5 recordsLinked to original sources

bioRxiv2026

Uncovering the multifaceted mechanism of action of a historical antimicrobial

Natural products have provided most of our modern pharmacopoeia, serving as active molecules or scaffolds for active molecules. Their use in drug development is often inspired by their traditional or historical medical use. For many decades, this discovery pipeline has focused on identifying a single molecule responsible for much of the biological activity of a raw natural product preparation (e.g. a whole-plant extract) and scoping this molecule for clinical potential. However, it is increasingly realised that historical/traditional remedies with significant biological activity may owe this activity to the combined action of multiple molecules. Concomitantly, microbiologists increasingly argue that effectively fighting antimicrobial-resistant infections will rely on combination therapies that combine multiple antimicrobials and/or adjuvant molecules. We previously reconstructed a complex historical remedy, Bald's eyesalve. Our reconstruction of this remedy had strong antibiofilm activity, which relied on the presence of multiple ingredients. Here, we report that Bald's eyesalve has multiple antibacterial effects on exemplar Gram-positive (Staphylococcus aureus) and Gram-negative (Acinetobacter baumannii) pathogens. Bald's eyesalve disrupts bacterial membrane integrity; inhibits expression of genes associated with bacterial adhesins, virulence factors and efflux pumps in both S. aureus and A. baumannii; inhibits quorum sensing in S. aureus; and causes downregulation of genes involved in de novo nucleotide biosynthesis in S. aureus. Lastly, we show that this multifaceted mechanism of action makes it difficult for S. aureus, A. baumannii, and Pseudomonas aeruginosa to evolve resistance against Bald's eyesalve. Bald's eyesalve could be used to identify a defined cocktail of natural products suitable for preclinical testing as a multi-target antibacterial preparation to which resistance may arise more slowly than current single-molecule antibiotics.

microbiology↗

bioRxiv2024

Construction of a drug sensitised Candida auris strain

Candida auris is an emerging pathogenic fungus causing outbreaks of invasive disease in healthcare facilities worldwide with the majority of clinical isolates demonstrating intrinsic resistance to multiple drug classes. Therefore, there is a pressing need for new antifungals, but screening in wild-type C. auris strains may miss scaffolds which would be good subjects for med-chem projects as antifungals. Work presented here indicates that deletion of CDR1 and MDR1 in C. auris, respectively encoding an ATP-binding Cassette and a Major Facilitator Superfamily efflux pump, generates a strain that is hypersensitised to drugs and can act as a platform for antifungal drug screening. The cdr1{Delta}mdr1{Delta} mutant was 64- and 8- times more sensitive to fluconazole and voriconazole, respectively, compared with the wild-type strain. In a pilot study using a 2,000 compound library, use of the cdr1{Delta}mdr1{Delta} mutant identified over twice as many compounds compared to wild-type. When assessing the capacity to form biofilms, there was a modest difference in biomass between the wild-type and cdr1{Delta}mdr1{Delta} mutant, but there was little to no statistically significant difference observed when using a colorimetric dye that measured metabolic activity. Little to no statistically significant difference was observed between wild-type and the efflux pump mutant in virulence, as judged by the larval Galleria mellonella infectivity assay. Accordingly, the cdr1{Delta}mdr1{Delta} mutant will be useful when screening for drugs that limit formation of biofilms or limit fungal virulence, as these two properties are unaffected when drug efflux is compromised.

microbiology↗

bioRxiv2021

An assessment of the evidence for antibacterial activity of stinging nettle (Urtica dioica) extracts

Stinging nettles (Urtica spp.) have been used in a diverse range of traditional and historical medicines from around the world for the treatment of skin diseases, wounds, urinary disorders, respiratory diseases, bone and joint pain, anaemia and other circulatory problems, as well as in cosmetic preparations for skin and haircare. As part of an interdisciplinary exploration of nettle-based remedies, we performed a systematic review of published evidence for the antimicrobial activity of Urtica spp. extracts against bacteria and fungi that commonly cause skin, soft tissue and respiratory infections. We focussed on studies in which minimum inhibitory concentration (MIC) assays of U. dioica were conducted on the common bacterial opportunistic pathogens Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae and Staphylococcus aureus. No studies used fresh leaves (all were dried prior to use), and no studies prepared nettles in weak acid (corresponding to vinegar) or in fats/oils, which are common combinations in historical and traditional preparations. We addressed this gap by conducting new antibacterial tests of extracts of fresh U. dioica leaves prepared in vinegar, butter or olive oil against P. aeruginosa and S. aureus. Our systematic review and additional experimental data leads us to conclude that there is no strong evidence for nettles containing molecules with clinically useful antimicrobial activity. It seems most likely that the utility of nettles in traditional topical preparations for wounds may simply be as a "safe" absorbent medium for keeping antibacterial (vinegar) or emollient (oils) ingredients at the treatment site. Data SummaryAll data relating to the systematic review are supplied in the Datasets and Supplementary tables contained in the Supporting Data file.

microbiology↗

bioRxiv2020

The safety profile of Bald's eyesalve for the treatment of bacterial infections

The rise in antimicrobial resistance has prompted the development of alternatives, such as plant-derived compounds, to combat bacterial infections. Balds eyesalve, a remedy used in the Early Medieval period, has previously been shown to have efficacy against Staphylococcus aureus grown in an in vitro model of soft tissue infection. This remedy also had bactericidal activity against methicillin-resistant S. aureus (MRSA) in a chronic mouse wound. However, the safety profile of Balds eyesalve has not yet been demonstrated, and this is vital before testing in humans. Here, we determined the safety potential of Balds eyesalve using in vitro, ex vivo, and in vivo models representative of skin or eye infections. We also confirmed that Balds eyesalve is active against an important eye pathogen, Neisseria gonorrhoeae. Low levels of cytotoxicity were observed in eyesalve-treated cell lines representative of skin and immune cells. Results from a bovine corneal opacity and permeability test demonstrated slight irritation to the cornea that resolved within 10 minutes. The slug mucosal irritation assay revealed that a low level of mucus was secreted by slugs exposed to eyesalve, indicating mild mucosal irritation. We obtained promising results from mouse wound closure experiments; no visible signs of irritation or inflammation were observed. Our results suggest that Balds eyesalve could be tested further on human volunteers to assess safety for topical application against bacterial infections. ImportanceAlternative treatment for bacterial infections are needed to combat the ever increasing repertoire of bacteria resistant to antibiotics. A medieval plant-based remedy, Balds eyesalve, shows promise as a substitute for the treatment of these infections. For any substance to be effective in the treatment of bacterial infections in humans, it is important to consider the safety profile. This is a key consideration in order to have the necessary regulatory approval. We demonstrate the safety profile of Balds eyesalve using a variety of models, including whole-organ and whole-animal models. Our results show that Balds eyesalve is mildly toxic to cultured human cells, but potentially suitable for patch tests on healthy human volunteers to assess safety for later clinical trials. Our work has the potential to transform the management of diseases caused by bacterial infections, such as diabetic foot ulcers, through topical application of a natural product cocktail based on Balds eyesalve.

microbiology↗

bioRxiv2020

Anti-biofilm efficacy of a medieval treatment for bacterial infection requires the combination of multiple ingredients.

Novel antimicrobials are urgently needed to combat the increasing occurrence of drug-resistant bacteria and to overcome the inherent difficulties in treating biofilm-associated infections. Research into natural antimicrobials could provide candidates to fill the antibiotic discovery gap, and the study of plants and other natural materials used in historical infection remedies may enable further discoveries of natural products with useful antimicrobial activity. We previously reconstructed a 1,000-year-old remedy containing onion, garlic, wine, and bile salts, which is known as Balds eyesalve, and showed it to have promising antibacterial activity. In this paper, we have found this remedy has bactericidal activity against a range of Gram-negative and Gram-positive wound pathogens in planktonic culture and, crucially, that this activity is maintained against Acinetobacter baumannii, Stenotrophomonas maltophilia, Staphylococcus aureus, Staphylococcus epidermidis and Streptococcus pyogenes in a model of soft-tissue wound biofilm. While the presence of garlic in the mixture is sufficient to explain activity against planktonic cultures, garlic alone has no activity against biofilms. We have found the potent anti-biofilm activity of Balds eyesalve cannot be attributed to a single ingredient and requires the combination of all ingredients to achieve full activity. Our work highlights the need to explore not only single compounds but also mixtures of natural products for treating biofilm infections. These results also underline the importance of working with biofilm models when exploring natural products for the anti-biofilm pipeline. ImportanceBacteria can live in two ways, as individual planktonic cells or as a multicellular biofilm. Biofilm helps protect bacteria from antibiotics and makes them much harder to treat. Both the biofilm lifestyle and the evolution of antibiotic resistance mean we urgently need new drugs to treat infections. Here, we show that a medieval remedy made from onion, garlic, wine, and bile can kill a range of problematic bacteria grown both planktonically and as biofilms. A single component of the remedy - allicin, derived from garlic - is sufficient to kill planktonic bacteria. However, garlic or allicin alone do nothing against bacteria when they form a biofilm. All four ingredients are needed to fully kill bacterial biofilm communities, hinting that these ingredients work together to kill the bacteria. This suggests that future discovery of antibiotics from natural products could be enhanced by studying combinations of ingredients, rather than single plants or compounds.

microbiology↗