Clinical microbiology study of diabetic foot ulcer in Iran; pathogens and antibacterial susceptibility

The aim of this study was to investigate microbial pathogens and their antibiotic susceptibility profile in infected diabetic foot ulcers in Iranian patients. This was a one-year cross sectional study on diabetic patients with infected diabetic foot ulcer at Shariati Teaching Hospital, Tehran, Iran. Grade of ulcer was determined by Wagner's criteria. Specimens were obtained from the base of ulcer, deep part of the wound or aspiration and were tested with gram staining and antibacterial susceptibility was determined with both disk diffusion and E-Test methods. Total of 546 pathogens were isolated from 165 ulcers of 149 patients. Gram positive aerobes including Enterococcal species and methicillin resistant Staphylococcus aureus (S. aureus) (21.4 and 19.4%, respectively) were identified as the most common pathogens followed by Gram negative isolates including Escherichia coli and Pseudomonas-aeruginosa (12.6 and 5.4%, respectively). The majority of wounds were classified as Wagner grades 2 and 3 (15.7 and 75.7%). Appropriate empiric treatment to cover both these Gram positive and Gram negative pathogens is crucially important

Statins use and risk of breast cancer recurrence and death: A systematic review and meta-analysis of observational studies

Purpose. Statins are widely prescribed drugs for lowering cholesterol. Some studies have suggested that statins can prevent breast cancer recurrence and reduce mortality rate. However they are not conclusive. Present systematic review and meta-analysis of published cohort studies was conducted to determine the effects of statins intake and risk of breast cancer recurrence and mortality rate. Methods. Online databases (PubMed, Embase, Scopus, EBSCO and Cochrane Collaboration) were searched through October 2014. Pooled relative risks and 95 confidence intervals were calculated with random-effects. Results. A total of 8 cohort studies (4 for recurrence 2 for mortality and 2 for both) involving 124669 participants with breast cancer were eligible. Our results suggest a significant reduction in recurrence (OR= 0.79. I2= 38) and death (OR = 0.84, I2 = 8.58) among statin users. Conclusion. Our meta-analysis suggests that breast cancer patients will benefit from statin intake, however from these cohorts we are unable to differentiate between various statins in terms of effectiveness and duration of use. We highly propose conducting randomized clinical trials. © 2016, Canadian Society for Pharmaceutical Sciences. All rights reserved

Analogues of Arylamide Phenylpiperazine Ligands To Investigate the Factors Influencing D3 Dopamine Receptor Bitropic Binding and Receptor Subtype Selectivity

We have previously reported on the ability of arylamide phenylpiperazines to bind selectively to the D3 versus the D2 dopamine receptor subtype. For these studies, we used LS-3-134 as the prototypic arylamide phenylpiperazine ligand because it binds with high affinity at D3 dopamine receptor (0.17 nM) and exhibits >150-fold D3 vs D2 receptor binding selectivity. Our goal was to investigate how the composition and size of the nonaromatic ring structure at the piperazine position of substituted phenylpiperazine analogues might influence binding affinity at the human D2 and D3 dopamine receptors. Two factors were identified as being important for determining the binding affinity of bitropic arylamide phenylpiperazines at the dopamine D3 receptor subtype. One factor was the strength of the salt bridge between the highly conserved residue Asp^3.32 with the protonated nitrogen of the nonaromatic ring at the piperazine position. The second factor was the configuration of the unbound ligand in an aqueous solution. These two factors were found to be related to the logarithm of the affinities using a simple correlation model, which could be useful when designing high affinity subtype selective bitropic ligands. While this model is based upon the interaction of arylamide phenylpiperazines with the D2 and D3 D2-like dopamine receptor subtypes, it provides insights into the complexity of the factors that define a bitropic mode of the binding at GPCRs

A Quick Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors*.

The COVID-19 pathogen, SARS-CoV-2, requires its main protease (SC2MPro ) to digest two of its translated long polypeptides to form a number of mature proteins that are essential for viral replication and pathogenesis. Inhibition of this vital proteolytic process is effective in preventing the virus from replicating in infected cells and therefore provides a potential COVID-19 treatment option. Guided by previous medicinal chemistry studies about SARS-CoV-1 main protease (SC1MPro ), we have designed and synthesized a series of SC2MPro inhibitors that contain β-(S-2-oxopyrrolidin-3-yl)-alaninal (Opal) for the formation of a reversible covalent bond with the SC2MPro active-site cysteine C145. All inhibitors display high potency with Ki values at or below 100 nM. The most potent compound, MPI3, has as a Ki value of 8.3 nM. Crystallographic analyses of SC2MPro bound to seven inhibitors indicated both formation of a covalent bond with C145 and structural rearrangement from the apoenzyme to accommodate the inhibitors. Virus inhibition assays revealed that several inhibitors have high potency in inhibiting the SARS-CoV-2-induced cytopathogenic effect in both Vero E6 and A549/ACE2 cells. Two inhibitors, MPI5 and MPI8, completely prevented the SARS-CoV-2-induced cytopathogenic effect in Vero E6 cells at 2.5-5 μM and A549/ACE2 cells at 0.16-0.31 μM. Their virus inhibition potency is much higher than that of some existing molecules that are under preclinical and clinical investigations for the treatment of COVID-19. Our study indicates that there is a large chemical space that needs to be explored for the development of SC2MPro inhibitors with ultra-high antiviral potency

Deamination of 6-Aminodeoxyfutalosine in Menaquinone Biosynthesis by Distantly Related Enzymes

Proteins of unknown function belonging to cog1816 and cog0402 were characterized. Sav2595 from Steptomyces avermitilis MA-4680, Acel0264 from Acidothermus cellulolyticus 11B, Nis0429 from Nitratiruptor sp. SB155-2 and Dr0824 from Deinococcus radiodurans R1 were cloned, purified, and their substrate profiles determined. These enzymes were previously incorrectly annotated as adenosine deaminases or chlorohydrolases. It was shown here that these enzymes actually deaminate 6-aminodeoxyfutalosine. The deamination of 6-aminodeoxyfutalosine is part of an alternative menaquinone biosynthetic pathway that involves the formation of futalosine. 6-Aminodeoxyfutalosine is deaminated by these enzymes with catalytic efficiencies greater than 10(5) M(−1) s(−1), K(m) values of 0.9 to 6.0 μM and k(cat) values of 1.2 to 8.6 s(−1). Adenosine, 2′-deoxyadenosine, thiomethyladenosine, and S-adenosylhomocysteine are deaminated at least an order of magnitude slower than 6-aminodeoxyfutalosine. The crystal structure of Nis0429 was determined and the substrate, 6-aminodeoxyfutalosine, was positioned in the active site, based on the presence of adventitiously bound benzoic acid. In this model Ser-145 interacts with the carboxylate moiety of the substrate. The structure of Dr0824 was also determined, but a collapsed active site pocket prevented docking of substrates. A computational model of Sav2595 was built based on the crystal structure of adenosine deaminase and substrates were docked. The model predicted a conserved arginine after β-strand 1 to be partially responsible for the substrate specificity of Sav2595