Screening of the novel antimicrobial drug, XF-73, against 2,527 species clinical isolates.

XF-73 (exeporfinium chloride) is a synthetic, di-cationic porphyrin derivative with rapid, potent bactericidal properties and a low propensity for engendering bacterial resistance. It is being developed clinically for the decolonization of in the nasal cavity to prevent post-operative staphylococcal infections. This study reports the minimum inhibitory concentration (MIC) of XF-73 in comparison to 22 antibiotics against a panel of >2,500 clinical isolates composed of 16 different Coagulase-positive and -negative species from 33 countries.

Antimicrobial effects of XF drugs against and its biofilms.

Compared with antibiotics for treating bacterial infections, there are a limited number of antifungal agents. This is due to several factors, including the difficulties of identifying suitable antifungals that target the fungal cell without damaging host cells, and the reduced rates of diagnosis of fungal infections compared with those caused by bacteria. The problem of treating fungal infections is exacerbated by an increasing incidence of antifungal resistance among human fungal pathogens.

Exeporfinium chloride (XF-73) nasal gel dosed over 24 hours prior to surgery significantly reduced nasal carriage in cardiac surgery patients: Safety and efficacy results from a randomized placebo-controlled phase 2 study.

We studied 83 cardiac-surgery patients with nasal carriage who received 4 intranasal administrations of XF-73 nasal gel or placebo <24 hours before surgery. One hour before surgery, patients exhibited a nasal carriage reduction of 2.5 log with XF-73 compared to 0.

Antibacterial and Antibiofilm Potency of XF Drugs, Impact of Photodynamic Activation and Synergy With Antibiotics.

With increasing incidence of antimicrobial resistance, there is an urgent need for novel and effective antibacterials. Destiny Pharma plc have developed a series of porphyrin-based XF drugs, some with dual mechanisms of antibacterial action. An innate mechanism acts through binding to the outer bacterial membrane and a separate, light-activated, photodynamic (PD) mechanism, acts the generation of reactive oxygen species.

Investigation of the potential for mutational resistance to XF-73, retapamulin, mupirocin, fusidic acid, daptomycin, and vancomycin in methicillin-resistant Staphylococcus aureus isolates during a 55-passage study.

XF-73 is a dicationic porphyrin drug with rapid Gram-positive antibacterial activity currently undergoing clinical trials for the nasal decolonization of Staphylococcus aureus, including methicillin-resistant Staphylococcus aureus (MRSA). In multistep (55-passage) resistance selection studies in the presence of subinhibitory concentrations of XF-73, retapamulin, mupirocin, fusidic acid, and vancomycin against four Network on Antimicrobial Resistance in Staphylococcus aureus MRSA strains, there was no >4-fold increase in the MIC for XF-73 after 55 passages. In contrast, there was an increase in the MICs for retapamulin (from 0.

The novel antibacterial drug XF-70 is a potent inhibitor of Staphylococcus aureus infection of the burn wound.

The authors report the findings of in vivo studies of XF-70 (a novel, dicationic porphyrin) against Staphylococcus aureus in a murine model of a burn wound infection. Mice received a 15% total body scald burn wound, which were inoculated with S. aureus (1.

In vitro activity of XF-73, a novel antibacterial agent, against antibiotic-sensitive and -resistant Gram-positive and Gram-negative bacterial species.

The antibacterial activity of XF-73, a dicationic porphyrin drug, was investigated against a range of Gram-positive and Gram-negative bacteria with known antibiotic resistance profiles, including resistance to cell wall synthesis, protein synthesis, and DNA and RNA synthesis inhibitors as well as cell membrane-active antibiotics. Antibiotic-sensitive strains for each of the bacterial species tested were also included for comparison purposes. XF-73 was active [minimum inhibitory concentration (MIC) 0.

XF-70 and XF-73, novel antibacterial agents active against slow-growing and non-dividing cultures of Staphylococcus aureus including biofilms.

Objectives: Slow-growing and non-dividing bacteria exhibit tolerance to many antibiotics. However, membrane-active agents may act against bacteria in all growth phases. We sought to examine whether the novel porphyrin antibacterial agents XF-70 and XF-73, which have rapid membrane-perturbing activity against Staphylococcus aureus, retained antistaphylococcal activity against growth-attenuated cells.

XF-73, a novel antistaphylococcal membrane-active agent with rapid bactericidal activity.

Objectives: XF-73 is a novel porphyrin antibacterial agent previously reported to inhibit a range of gram-positive bacterial species, including Staphylococcus aureus. Its mode of action is unknown. Using S.

Microarray analysis of senescent vascular smooth muscle cells: A link to atherosclerosis and vascular calcification.

Little is known about the senescent phenotype of human vascular smooth muscle cells (VSMCs) and the potential involvement of senescent VSMCs in age-related vascular disease, such as atherosclerosis. As such, VSMCs were grown and characterised in vitro to generate senescent VSMCs needed for microarray analysis (Affymetrix). Comparative analysis of the transcriptome profiles of early (14 CPD) and late (39-42 CPD) passage VSMCs found a total of 327 probesets called as differentially expressed: 149 are up-regulated in senescence and 178 repressed (p-value<0.

Cyclin D1 overexpression permits the reproducible detection of senescent human vascular smooth muscle cells.

The senescence of mitotic cells is hypothesized to play a causal role in organismal aging. Cultures of normal human cells become senescent in vitro as a result of a continuous decline in the mitotic fraction from cell turnover. However, one potential barrier to the evaluation of the frequency and distribution of senescent cells in tissues is the absence of a panel of robust markers for the senescent state.

In vivo assessment of the osteointegrative potential of phosphatidylserine-based coatings.

The successful implantation of titanium-based implants for orthopaedic and dental applications is often hindered because of their mobility, which arises because of a lack of direct binding of the metal surface to the mineral phase of the surrounding bone. Ceramic coatings, although ensuring the integration of the implant within the tissue, are unstable and carry risks of delamination and of failure. Recently, a novel biomimetic approach has been developed where porous titanium implants are coated with calcium-binding phospholipids able to catalyse the nucleation of discrete apatite crystals after only 30 min incubation in simulated body fluids.

Calcium-binding phospholipids as a coating material for implant osteointegration.

Among the many biomolecules involved in the bone mineralization processes, anionic phospholipids play an important role because of their ability to bind calcium. In particular, phosphatidylserine is a natural component of the plasmalemma and of the matrix vesicles generated from the osteoblast membrane to create nucleation centres for calcium phosphate crystal precipitation. In the present work, we demonstrate that calcium-binding phospholipids can be used as biomimetic coating materials for improving the osteointegration of metal implants.

Assessing the in vitro cell based ocular compatibility of contact lens materials.

A series of in vitro assays for determining the biocompatibility of ocular biomaterials have been developed and used to assess the differences in performance of omafilcon A, etafilcon A and nelfilcon A contact lens materials. The assays assessed bacterial attachment, macrophage adhesion, granulocyte adhesion and activation, epithelial cell adhesion and corneal cell contact damage. Overall, omafilcon A was found to be more biocompatible than the other materials although there was no significant difference between the epithelial cell adhesion and granulocyte adhesion and activation on any of the hydrogels.

The stereo inversion of 2-arylpropionic acid non-steroidal anti-inflammatory drugs and structurally related compounds by Verticillium lecanii.

The fungus Verticillium lecanii has previously been shown to be capable of inverting the chirality of ibuprofen and 2-phenylpropionic acid from the (R)-enantiomer to the corresponding (S)-antipode, a phenomenon also observed in mammalian systems including man. An investigation is reported here into the substrate specificity of the enzyme system present in V. lecanii using the following 2-arylpropionic acids: ibuprofen, ketoprofen, indoprofen, suprofen, flurbiprofen and fenoprofen, together with the structurally related compounds 2-phenylbutyric acid, 2-phenoxypropionic acid, mandelic acid, atrolactic acid, etodolac and alpha-methoxyphenylpropionic acid.

Indirect enantiomeric separation of 2-arylpropionic acids and structurally related compounds by reversed phase HPLC.

A reversed-phase high-performance liquid chromatographic method, using an organic modifier-phosphate buffered mobile phase, for the determination of the enantiomeric composition of 2-arylpropionic acids and other structurally related compounds in microbial media is described. The method is based on the resolution of diastereoisomeric amides formed from the reaction of the arylpropionic acid with either (-)-(S)-alpha-methylbenzylamine or (-)-(S)-1-(naphthen-1-yl)ethylamine in the presence of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide HCl and 1-hydroxybenzotriazole and incorporating an internal standard. The addition of sodium pentanesulphonate to the mobile phase as an ion-pairing agent was necessary to remove unreacted amine to avoid rapid column deterioration.

Optimization of the chiral inversion of 2-phenylpropionic acid by Verticillium lecanii.

Previous studies have demonstrated that Verticillium lecanii might be used as a microbial model of the inversion of 2-arylpropionic acids in man. This paper describes the optimization of the inversion process in respect of culture medium, pH, cell density and substrate concentration. The study demonstrates that optimum inversion occurs in Sørensen's phosphate buffer at pH 5.

A mechanistic investigation of the microbial chiral inversion of 2-phenylpropionic acid by Verticillium lecanii.

Previous investigations have described the development of nongrowing suspensions of Verticillium lecanii as a microbial model of the mammalian chiral inversion of the 2-arylpropionic acids (2-APAs). Mechanistic studies in mammals have shown that inversion involves loss of the alpha-methine proton but retention of the original atoms at the beta-methyl position, and a mechanism has been proposed involving enzymatic epimerisation of acyl-CoA thioester derivatives of the substrate. Inversion of the 2-APAs by V.

A novel pathway for the catabolism of 4-nitrotoluene by Pseudomonas.

Eleven strains of Pseudomonas were isolated by selective enrichment on 4-nitrotoluene (4NT). They all utilized 4NT, 4-nitrobenzyl alcohol (4NBA) or 4-nitrobenzoate (4NBZate) as sole sources of carbon and nitrogen. One strain, TW3, was used for more detailed studies.