The Efficacy of Tetrasodium EDTA on Biofilms.

The aetiology of delayed wound healing characteristic of a chronic wound is relatively unknown but is thought to be due to a combination of the patient's underlying pathophysiology and external factors including infection and biofilm formation. The invasion of the wound by the hosts' resident microbiome and exogenous microorganisms can lead to biofilm formation. Biofilms have increased tolerance to antimicrobial interventions and constitute a concern to chronic wound healing. Consequently, anti-biofilm technologies with proven efficacy in areas outside of wound care need evaluation to determine whether their efficacy could be relevant to the control of biofilms in wounds. The aim of this study was to assess the anti-biofilm capabilities of tetrasodium EDTA (t-EDTA) as a stand-alone liquid and when incorporated in low concentrations into wound dressing prototypes. Results demonstrated that a low concentration of t-EDTA (4%) solution was able to kill Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), S. epidermidis, Pseudomonas aeruginosa and Enterococcus faecalis within in vitro biofilms after a 24-h contact time. The incorporation of low levels of t-EDTA into prototype fibrous wound dressings resulted in a 3-log reduction of bacteria demonstrating its microbicidal ability. Furthermore, hydrogels incorporating only a 0.2% concentration of t-EDTA (at preservative levels) caused a small reduction in biofilm. In conclusion, these studies show that t-EDTA as a stand-alone agent is an effective anti-biofilm agent in vitro. We have demonstrated that t-EDTA is compatible with numerous wound dressing platforms. EDTA could provide an essential tool to manage biofilm-related infections and should be considered as an anti-biofilm agent alone or in combination with other antimicrobials or technologies for increased antimicrobial performance in recalcitrant wounds.

Salmonella Virchow isolates from human and avian origins in England--molecular characterization and infection of epithelial cells and poultry.

AIMS: To characterize 12 Salmonella Virchow isolates from human and avian sources to begin to determine the genetic relationships within the serovar, determine its capacity to invade and induce inflammatory responses in human intestinal epithelial cells and investigate its ability to colonize the chicken gastrointestinal tract. METHODS AND RESULTS: Multi-Locus Sequence Typing (MLST) revealed that 11 isolates belonged to sequence type 16 (ST16). Pulsed Field Gel Electrophoresis (PFGE) grouped the isolates into two main clusters. All isolates contained genes associated with virulence determined through PCR virulotyping. All the S. Virchow isolates had the ability to invade human epithelial cells and elicit high levels of production of the pro-inflammatory chemokine interleukin-8 (IL-8). Experimental infection of poultry showed S. Virchow colonizes the caeca and spleen. CONCLUSIONS: Isolates within the serovar show high levels of genetic relatedness regardless of the source. The data indicates S. Virchow is an invasive and inflammatory serovar, consistent with its association with invasive salmonellosis in humans. SIGNIFICANCE AND IMPACT OF THE STUDY: The poultry infection experiment included in this study shows S. Virchow can colonize the gastrointestinal tract rapidly and to high levels with the chickens showing no clinical signs of infection. The asymptomatic colonization of chickens indicates an increased ability of S. Virchow to enter the food chain undetected and cause human salmonellosis which because of the invasive and inflammatory nature of S. Virchow seen during the Caco2 invasion assay and previous studies showing its invasive nature in humans and increasing resistance to antibiotics is a public health concern.

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 1.

The alarming reduction in drug effectiveness against bacterial infections has created an urgent need for the development of new antibacterial agents that circumvent bacterial resistance mechanisms. We report here a series of DNA gyrase and topoisomerase IV inhibitors that demonstrate potent activity against a range of Gram-positive and selected Gram-negative organisms, including clinically-relevant and drug-resistant strains. In part 1, we present a detailed structure activity relationship (SAR) analysis that led to the discovery of our previously disclosed compound, REDX05931, which has a minimum inhibitory concentration (MIC) of 0.06 µg mL-1 against fluoroquinolone-resistant Staphylococcus aureus. Although in vitro hERG and CYP inhibition precluded further development, it validates a rational design approach to address this urgent unmet medical need and provides a scaffold for further optimisation, which is presented in part 2.

Rational design, synthesis and testing of novel tricyclic topoisomerase inhibitors for the treatment of bacterial infections part 2.

Building on our previously-reported novel tricyclic topoisomerase inhibitors (NTTIs), we disclose the discovery of REDX07965, which has an MIC90 of 0.5 µg mL-1 against Staphylococcus aureus, favourable in vitro pharmacokinetic properties, selectivity versus human topoisomerase II and an acceptable toxicity profile. The results herein validate a rational design approach to address the urgent unmet medical need for novel antibiotics.