Biology subjects

Cornbill, C.

Publications and source records attributed to Cornbill, C..

3 recordsLinked to original sources

bioRxiv2026

Tetrasodium EDTA disrupts Pseudomonas aeruginosa membrane integrity, shows suppressed resistance evolution and reduced cytotoxicity compared to meropenem

Pseudomonas aeruginosa remains one of the most important clinical pathogens for which new drugs are needed, due to its resistance machinery. Consequently, there is an increasing effort to develop new and effective treatments against this pathogen. We recently showed that tetrasodium ethylenediaminetetraacetic acid (tEDTA) exhibits promising antibacterial and antibiofilm activity against P. aeruginosa in advanced biofilm models. tEDTA is known to chelate divalent cations, with predicted effects on the outer membrane; however, a full understanding of how this kills P. aeruginosa is lacking. Also, it is currently not clear how slowly or rapidly P. aeruginosa will evolve resistance to this treatment. Using membrane disruption assays and RNA-seq, we showed that tEDTA disrupts bacterial membrane potential and permeabilises P. aeruginosa membranes. RNA-seq revealed the significant upregulation of genes involved in the transport of iron, phosphate, potassium, and magnesium ion. The arnABCD operon which is involved in lipid A biosynthesis was also upregulated. Using a 7-day evolutionary ramp approach, we showed that P. aeruginosa could not evolve resistance to tEDTA under strong selection. Lastly, we carried out a cytotoxicity assay with Human Epithelial type 2 (HEp-2) cells and showed that there was reduced cytotoxicity of tEDTA compared to meropenem. This study provides good insight into the mechanism of action of tEDTA and further evidence of its potential as an alternative to antibiotics for P. aeruginosa infections.

microbiology↗

bioRxiv2026

In vitro evolution of uropathogenic Escherichia coli to fosfomycin resistance in a 3D cultured human bladder microtissue model

In vitro studies of antimicrobial resistance (AMR) using laboratory growth media produce important, fundamental information. However, their inability to more closely replicate the in vivo environment limits the translational potential of this work. Here, we used a 3D cultured microtissue model which reflects the human bladder microenvironment to select for resistance to fosfomycin in two uropathogenic strains of Escherichia coli, UTI-34 and UTI-59. To assess the clinical relevance of the mutations produced, we screened the observed mutations in the fosfomycin-selected variants against a curated dataset of 14,163 E. coli genomes isolated from urine. The four independent fosfomycin-selected variants of UTI-34 contained diverse mutations, while the mutations in the five independent fosfomycin-selected variants of UTI-59 were more constrained. All variants contained mutations in glpT, uhpT, uhpA and uhpC, which are commonly linked to fosfomycin-resistance in clinical isolates of E. coli. Screening of the mutations against the 14,163 E. coli genomes from urine confirmed that four of these mutations were found as exact matches in the dataset, while other mutation types were confirmed at a regional and gene level. These mutations did not result in any collateral susceptibility or resistance to other antibiotics recommended for the treatment of urinary tract infections. The use of a human 3D microtissue model, which closely replicates the urothelial microenvironment to study AMR during urinary tract infection treatment, could improve the clinical relevance of in vitro AMR studies. This has the potential to provide a better understanding of how AMR is acquired and expressed, and inform new strategies to combat AMR.

microbiology↗

bioRxiv2025

Low concentrations of tetrasodium EDTA cause significant killing of biofilm-associated P. aeruginosa in high validity models of chronic wound and CF lung infections but not in a model of endotracheal tube colonisation

Pseudomonas aeruginosa is a pathogen notorious for its antimicrobial resistance and is currently classified as a high-priority pathogen for which new drugs are needed. Tetrasodium EDTA (tEDTA) is one of the new antimicrobial compounds that have been shown to have good antibacterial and antibiofilm efficacy against P. aeruginosa. Due to the diversity and highly drug-tolerant nature of P. aeruginosa biofilms in different infection environments, it is important to carry out pre-clinical testing of new antibiofilm agents against this pathogen in media and models that accurately mimic diverse infection environments. In this study, we used different high validity media and biofilm models that mimic chronic wounds, endotracheal tubes, and cystic fibrosis lung infections to assess the efficacy of tEDTA against P. aeruginosa biofilms. We report that different infection environments influence the susceptibility of both planktonic and biofilm forms of P. aeruginosa to tEDTA. The highest tolerance to tEDTA was observed in the media and biofilm model that mimics the endotracheal tube environment. In conclusion, we show that although different infection environments influence the efficacy of tEDTA against P. aeruginosa biofilms, it has good potential for use as an alternative antimicrobial in treating P. aeruginosa-associated biofilm infections.

microbiology↗