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. Three XF drugs (XF-73, XF-70, and DPD-207) have previously displayed innate bactericidal effects and a low propensity for microbial resistance, with XF-73 and XF-70 having a second, light-activated mechanism of action known as photodynamic therapy (PDT). In an effort to expand the repertoire of antifungal agents, this research assessed the
in vitro
activity of XF drugs via both mechanisms of action against six strains of the fungal pathogen
Candida albicans
in both planktonic and biofilm cultures. In addition, this research examined the effects of XF drug treatment on biofilms of
C. albicans
in a reconstituted human oral epithelium model. All
C
.
albicans
strains tested were susceptible to XF-73 and XF-70, with minimum inhibitory concentrations (MICs) between 0.25 µg/mL and 2 µg/mL; DPD-207 was less potent, with MICs between 4 µg/mL and 16 µg/mL, and light activation did not enhance these MICs. Complete biofilm eradication was not reported at the tested XF drug concentrations. However, live and dead staining of
C. albicans
cells in biofilms after XF drug treatment demonstrated that XF-73 and XF-70 were active against most
Candida
biofilms tested from 64 µg/mL; again, light activation did not enhance anti-biofilm activity.
Candida
biofilms were more resistant to DPD-207, with fungicidal effects occurring from 256 µg/mL. XF-73 and XF-70 reduced penetration of
C. albicans
biofilm into reconstituted human oral epithelium (RHOE) and resulted in less damage (as determined by reduced lactate dehydrogenase release) than untreated biofilms. Overall, the results highlight the potential of XF drugs as new drugs for the management of topical infections caused by
C. albicans
. Further studies are warranted on the development of XF drugs as antifungals, particularly for XF-73 and XF-70.
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. aureus as a model organism we sought to examine the basis of its antibacterial activity. Methods The effects of XF-73 on the growth and survival of S. aureus SH1000 were investigated by viable count and culture absorbance techniques. Inhibition of macromolecular synthesis and disruption of membrane integrity after exposure to XF-73 were examined by radiolabelling experiments, the BacLight fluorescent dye assay and measurement of K+ and ATP leakage from the cell. The effect of XF-73 on a staphylococcal coupled transcription–translation system was also investigated. Results XF-73 was rapidly bactericidal against S. aureus SH1000 and demonstrated more rapid killing kinetics than all other comparator agents when tested at an equivalent multiple (4×) of the MIC. Exposure of S. aureus to XF-73 for 10 min completely inhibited DNA, RNA and protein synthesis. XF-73 had no effect on transcription and translation in vitro. Cells exposed to XF-73 gave a positive response in the BacLight assay, which detects membrane damage. The drug also caused substantial loss of K+ and ATP from the cell, but did not promote bacterial lysis. Conclusions XF-73 exhibited rapid membrane-perturbing activity, which is likely to be responsible for inhibition of macromolecular synthesis and the death of staphylococci exposed to the drug.
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. Methods The killing kinetics of XF-70, XF-73 and various comparator agents against exponential phase cultures of S. aureus SH1000 were compared with effects on cells held at 4°C, non-growing cultures expressing the stringent response induced by mupirocin and bacteria in the stationary phase. Biofilms of S. aureus SH1000 were generated with the Calgary device to examine the activities of XF-70 and XF-73 under a further system exhibiting diminished bacterial growth. Results Cold culture, stringent response and stationary phase cultures remained susceptible to XF-70 and XF-73, which caused ≥5 log reductions in viability over 2 h. During this period the most active comparator agents (chlorhexidine and cetyltrimethylammonium bromide) only promoted a 3 log drop in viability. XF-70 and XF-73 were also highly active against biofilms, with both agents exhibiting low biofilm MICs (1 mg/L) and minimum biofilm eradication concentrations (2 mg/L). Conclusions XF-70 and XF-73 remained highly active against various forms of slow-growing or non-dividing S. aureus. The results support the hypothesis that membrane-active agents may be particularly effective in eradicating slow- or non-growing bacteria and suggest that XF-70 and XF-73 could be utilized to treat staphylococcal infections where the organisms are only dividing slowly, such as biofilm-associated infections of prosthetic devices.
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. The present work assesses the osteointegrative potential of this new class of coatings in an in vivo rabbit model and compares its performance with those of bare porous titanium and hydroxyapatite-coated titanium. The data obtained show that phosphatidylserine-based coatings, whilst resorbing, drive the growing bone into apposition with the metal surface. This is in contrast to the case of bare titanium.
To estimate the number of deaths attributable to diabetes in 20–79-year-old adults in 2019.
The following were used to estimate the number of deaths attributable to diabetes: all-cause mortality ...estimates from the World Health Organization life table, country level age- and sex-specific estimates of diabetes prevalence in 2019 and relative risks of death in people with diabetes compared to people without diabetes.
An estimated 4.2 million deaths among 20–79-year-old adults are attributable to diabetes. Diabetes is estimated to contribute to 11.3% of deaths globally, ranging from 6.8% (lowest) in the Africa Region to 16.2% (highest) in the Middle East and North Africa. About half (46.2%) of the deaths attributable to diabetes occur in people under the age of 60 years. The Africa Region has the highest (73.1%) proportion of deaths attributable to diabetes in people under the age of 60 years, while the Europe Region has the lowest (31.4%).
Diabetes is estimated to contribute to one in nine deaths among adults aged 20–79 years. Prevention of diabetes and its complications is essential, particularly in middle-income countries, where the current impact is estimated to be the largest. Contemporary data from diverse populations are needed to validate these estimates.
Debate over the Late Quaternary megafaunal extinctions has focussed on whether human colonisation or climatic changes were more important drivers of extinction, with few extinctions being ...unambiguously attributable to either. Most analyses have been geographically or taxonomically restricted and the few quantitative global analyses have been limited by coarse temporal resolution or overly simplified climate reconstructions or proxies. We present a global analysis of the causes of these extinctions which uses high-resolution climate reconstructions and explicitly investigates the sensitivity of our results to uncertainty in the palaeological record. Our results show that human colonisation was the dominant driver of megafaunal extinction across the world but that climatic factors were also important. We identify the geographic regions where future research is likely to have the most impact, with our models reliably predicting extinctions across most of the world, with the notable exception of mainland Asia where we fail to explain the apparently low rate of extinction found in in the fossil record. Our results are highly robust to uncertainties in the palaeological record, and our main conclusions are unlikely to change qualitatively following minor improvements or changes in the dates of extinctions and human colonisation.
The late Quaternary period saw the rapid extinction of the majority of the world's terrestrial megafauna. The cause of these dramatic losses, especially the relative importance of climatic change and ...the impacts of newly arrived people, remains highly controversial, with geographically restricted analyses generating conflicting conclusions. By analyzing the distribution and timing of all megafaunal extinctions in relation to climatic variables and human arrival on five landmasses, we demonstrate that the observed pattern of extinctions is best explained by models that combine both human arrival and climatic variables. Our conclusions are robust to uncertainties in climate data and in the dates of megafaunal extinctions and human arrival on different landmasses, and strongly suggest that these extinctions were driven by both anthropogenic and climatic factors.
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. Relatively thick phosphatidylserine-based coatings were deposited on titanium coupons by dip-coating. Upon dehydration in a simulated body fluid phospholipids were quickly crosslinked by calcium and re-arranged into a three-dimensional matrix able to induce rapid formation of a calcium phosphate mineral phase. The rate of mineralization was shown to be dependent on the adopted coating formulation. In the attempt to closely mimic the cell membrane composition, heterogeneous formulations based on the mixing of anionic phospholipids (either phosphatidylserine or phosphatidylinositol) with phosphatidylcholine and cholesterol were synthesized. However, surface plasmon resonance studies as well as scanning electron microscopy and elemental analysis demonstrated that the homogeneous phosphatidylserine coating was a more effective calcification environment than the heterogeneous formulations.
PDF
