Oritavancin exhibits dual mode of action to inhibit cell-wall biosynthesis in Staphylococcus aureus

Solid-state NMR measurements performed on intact whole cells of Staphylococcus aureus labeled selectively in vivo have established that des-N-methylleucyl oritavancin (which has antimicrobial activity) binds to the cell-wall peptidoglycan, even though removal of the terminal N-methylleucyl residue destroys the d-Ala-d-Ala binding pocket. By contrast, the des-N-methylleucyl form of vancomycin (which has no antimicrobial activity) does not bind to the cell wall. Solid-state NMR has also determined that oritavancin and vancomycin are comparable inhibitors of transglycosylation, but that oritavancin is a more potent inhibitor of transpeptidation. This combination of effects on cell-wall binding and biosynthesis is interpreted in terms of a recent proposal that oritavancin-like glycopeptides have two cell-wall binding sites: the well-known peptidoglycan d-Ala-d-Ala pentapeptide stem terminus and the pentaglycyl bridging segment. The resulting dual mode of action provides a structural framework for coordinated cell-wall assembly that accounts for the enhanced potency of oritavancin and oritavancin-like analogues against vancomycin-resistant organisms.     

Drivers of promiscuous soybean associated rhizobia diversity in un-inoculated soil in Malawi

Increasing legume cultivation and yields on smallholder farms is challenged by low soil rhizobia bacteria populations and limited access to rhizobia inoculants. However, by understanding the environmental drivers of rhizobia diversity in un-inoculated soils to improve nodulation success for smallholder farmers. Soils were collected from 39 smallholder farms in the Ekwendeni region of northern Malawi. Soils were categorized by cropping history and analyzed for Mehlich-3 phosphorus, calcium, magnesium, potassium, iron, particle size distribution, organic matter (OM) content and pH. Rhizobia bacteria were isolated using Tropical Glycine cross (TGx) soybean (Glycine max) variety 1740-2F as a trap crop. Genomic fingerprints of extracted rhizobia were created using rep-PCR with the BOX A1R primer and diversity indexes calculated from resulting fingerprints. Genomic fingerprinting of rhizobia resulted in 32 clusters with 70 % fingerprint similarity. Soil OM and carbon strongly influenced the presence of 6 clusters, Ca of 4 clusters, pH of 3 clusters, and Mg, K, Clay of three clusters each. Recent soybean production resulted in a greater number of nodules (16) than other histories (10), and uncultivated soils had a different rhizobia community structure than cultivated soils. Soil rhizobia are subject to a complex ecology in which plant communities as well as OM, clay, and nutrient (Mg, K, Fe and P) content select for community structure. Identifying the drivers and preferred environments of high performing rhizobia strains could improve nodulation in low-input agriculture environments.     

Effect of beta-agonists on expression of calpain and calpastatin activity in skeletal muscle.

Administration of beta-adrenergic agonists to domestic species can lead to skeletal muscle hypertrophy, probably by reducing the rate of myofibrillar protein breakdown. Myofibrillar breakdown is associated with the calcium-dependent proteinase system (calpains I,II and calpastatin) whose activity also changes during beta-agonist treatment. A number of growth trials using the agonists cimaterol and clenbuterol with cattle, sheep, chicken and rat are reported which suggest a general mechanism whereby beta-agonists reduce calpain I activity, but increase calpain II and calpastatin activity in skeletal muscle. Parallel changes in specific mRNAs indicate that changes in gene expression or stabilisation of mRNA could in part explain the changes in activity.     

Describing termite assemblage structure in a Peruvian lowland tropical rain forest: a comparison of two alternative methods

Termites are frequently dominant invertebrate decomposers and bioturbators in lowland tropical forests and therefore strongly influence ecosystem processes favouring soil stability, porosity and nutrient retention. In this study, we provide the first spatially replicated dataset on termite assemblage composition, abundance and biomass in a Peruvian rainforest by sampling six separate plots. In addition, two alternative sampling methods (transect method-TM and quadrat method-QM), providing termite species density data, were compared among the plots. The relationships between a range of environmental and spatial variables and species composition were examined using canonical correspondence analysis variation partitioning. We found that the TM captured a higher proportion of the known species in the site (82 %) compared with the QM (66 %). In addition, 56 % of the species sampled by TM were common between the plots while only 18 % of species overlapped using the QM. The QM may therefore potentially have undersampled the species pool. Environmental variables were shown to explain a larger proportion of the species patterns than the spatial variables with elevation, soil temperature and distance to the river being the most important. We discuss the impacts of the environmental and spatial variables on termite species composition.     

Therapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry

Background

Two randomised, double-blind, placebo-controlled trials have investigated the efficacy of IV alpha-1 antitrypsin (AAT) augmentation therapy on emphysema progression using CT densitometry.

Methods

Data from these similar trials, a 2-center Danish-Dutch study (n = 54) and the 3-center EXAcerbations and CT scan as Lung Endpoints (EXACTLE) study (n = 65), were pooled to increase the statistical power. The change in 15^th percentile of lung density (PD15) measured by CT scan was obtained from both trials. All subjects had 1 CT scan at baseline and at least 1 CT scan after treatment. Densitometric data from 119 patients (AAT [Alfalastin^® or Prolastin^®], n = 60; placebo, n = 59) were analysed by a statistical/endpoint analysis method. To adjust for lung volume, volume correction was made by including the change in log-transformed total lung volume as a covariate in the statistical model.

Results

Mean follow-up was approximately 2.5 years. The mean change in lung density from baseline to last CT scan was -4.082 g/L for AAT and -6.379 g/L for placebo with a treatment difference of 2.297 (95% CI, 0.669 to 3.926; p = 0.006). The corresponding annual declines were -1.73 and -2.74 g/L/yr, respectively.

Conclusions

The overall results of the combined analysis of 2 separate trials of comparable design, and the only 2 controlled clinical trials completed to date, has confirmed that IV AAT augmentation therapy significantly reduces the decline in lung density and may therefore reduce the future risk of mortality in patients with AAT deficiency-related emphysema.

Trial registration

The EXACTLE study was registered in ClinicalTrials.gov as ''Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients''; ClinicalTrials.gov Identifier: {"type":"clinical-trial","attrs":{"text":"NCT00263887","term_id":"NCT00263887"}}NCT00263887.     

Antimicrobial peptide defenses in the salamander, Ambystoma tigrinum, against emerging amphibian pathogens

Skin peptides were collected from living Ambystoma tigrinum larvae and adults and tested against two emerging pathogens, Batrachochytrium dendrobatidis and the Ambystoma tigrinum virus (ATV), as well as bacteria isolated from A. tigrinum. Natural mixtures of skin peptides were found to inhibit growth of B. dendrobatidis, Staphylococcus aureus, and Klebsiella sp., but activity against ATV was unpredictable. Skin peptides collected from salamanders held at three environmentally relevant temperatures differed in activity against B. dendrobatidis. Activity of the A. tigrinum skin peptides was found to be strongly influenced by pH.