Evaluation of Genetically Inactivated Alpha Toxin for Protection in Multiple Mouse Models of Staphylococcus Aureus Infection.

Evaluation of Genetically Inactivated Alpha Toxin for Protection in Multiple Mouse Models of Staphylococcus aureus Infection.

PLoS One. 2013; 8(4): e63040
Brady RA, Mocca CP, Prabhakara R, Plaut RD, Shirtliff ME, Merkel TJ, Burns DL

Staphylococcus aureus is a major human pathogen and a leading cause of nosocomial and community-acquired infections. Development of a vaccine against this pathogen is an important goal. While S. aureus protective antigens have been identified in the literature, the majority have only been tested in a single animal model of disease. We wished to evaluate the ability of one S. aureus vaccine antigen to protect in multiple mouse models, thus assessing whether protection in one model translates to protection in other models encompassing the full breadth of infections the pathogen can cause. We chose to focus on genetically inactivated alpha toxin mutant HlaH35L. We evaluated the protection afforded by this antigen in three models of infection using the same vaccine dose, regimen, route of immunization, adjuvant, and challenge strain. When mice were immunized with HlaH35L and challenged via a skin and soft tissue infection model, HlaH35L immunization led to a less severe infection and decreased S. aureus levels at the challenge site when compared to controls. Challenge of HlaH35L-immunized mice using a systemic infection model resulted in a limited, but statistically significant decrease in bacterial colonization as compared to that observed with control mice. In contrast, in a prosthetic implant model of chronic biofilm infection, there was no significant difference in bacterial levels when compared to controls. These results demonstrate that vaccines may confer protection against one form of S. aureus disease without conferring protection against other disease presentations and thus underscore a significant challenge in S. aureus vaccine development. HubMed – drug

A Combination of Receptor-Based Pharmacophore Modeling & QM Techniques for Identification of Human Chymase Inhibitors.

PLoS One. 2013; 8(4): e63030
Arooj M, Sakkiah S, Kim S, Arulalapperumal V, Lee KW

Inhibition of chymase is likely to divulge therapeutic ways for the treatment of cardiovascular diseases, and fibrotic disorders. To find novel and potent chymase inhibitors and to provide a new idea for drug design, we used both ligand-based and structure-based methods to perform the virtual screening(VS) of commercially available databases. Different pharmacophore models generated from various crystal structures of enzyme may depict diverse inhibitor binding modes. Therefore, multiple pharmacophore-based approach is applied in this study. X-ray crystallographic data of chymase in complex with different inhibitors were used to generate four structure-based pharmacophore models. One ligand-based pharmacophore model was also developed from experimentally known inhibitors. After successful validation, all pharmacophore models were employed in database screening to retrieve hits with novel chemical scaffolds. Drug-like hit compounds were subjected to molecular docking using GOLD and AutoDock. Finally four structurally diverse compounds with high GOLD score and binding affinity for several crystal structures of chymase were selected as final hits. Identification of final hits by three different pharmacophore models necessitates the use of multiple pharmacophore-based approach in VS process. Quantum mechanical calculation is also conducted for analysis of electrostatic characteristics of compounds which illustrates their significant role in driving the inhibitor to adopt a suitable bioactive conformation oriented in the active site of enzyme. In general, this study is used as example to illustrate how multiple pharmacophore approach can be useful in identifying structurally diverse hits which may bind to all possible bioactive conformations available in the active site of enzyme. The strategy used in the current study could be appropriate to design drugs for other enzymes as well. HubMed – drug

Effects of aerobic exercise and drug therapy on blood pressure and antihypertensive drugs: a randomized controlled trial.

Afr Health Sci. 2013 Mar; 13(1): 1-9
Maruf F, Akinpelu A, Salako B

Although aerobic exercise has been shown to lower blood pressure (BP) in human beings, its additive BP-reducing effect on antihypertensive drug therapy seems to have been investigated in only laboratory animals.This study investigated the effects of aerobic dance combined with antihypertensive drugs on BP and number of antihypertensive drugs in individuals with hypertension.This open label randomised-controlled trial involved new-diagnosed male and female individuals with mild-to-moderate essential hypertension after at least four weeks of treatment. They were randomly assigned to drug therapy (Normoretic: Hydrochlorothiazide + amiloride hydrochloride, and Amlodipine) (control: n=33) and aerobic dance combined with drug therapy (exercise: n=30) groups. Intervention in each group lasted 12 weeks. BP was measured at baseline and during and pos-intervention. Number of antihypertensive drugs was recorded post-intervention.There were significant reductions in SBP at some periods of the intervention in the exercise group (p=0.000 to 0.002) and control group (p=0.001 to 0.002), and significant difference in DBP at some periods of the intervention in exercise group (p=0.000 to 0.003) and control group (p=0.000 to 0.001). SBP (p=0.066) and DBP (p=0.100) did not differ between the two groups post-12-week intervention. The BP control rates were similar between the exercises (56.7%) and control (35.5%) groups (p=0.075). Similarly, between-group difference in the number of drugs was not significant (p=0.511).This preliminary report demonstrates the tendency of aerobic dance to enhance BP control in individuals on two antihypertensive drugs without BP control. HubMed – drug