Loss of daptomycin susceptibility in clinical Staphylococcus epidermidis infection coincided with variants in WalK

Daptomycin (DAP) is key in treating multidrug-resistant Staphylococcus infections. Diminished susceptibility to DAP is emerging among Staphylococcus epidermidis strains although mechanisms for non-susceptibility (NS) remain poorly understood. We report a case of persistent S. epidermidis bacteremia in which loss of DAP susceptibility arose during prolonged treatment. Whole genome sequencing identified two mutations, Q371del and P415L, in a single-affected gene, WalK, that coincided with the emergence of DAP-NS. Protein modeling of the mutations predicted a disruption of WalK protein configuration. The emergence of mutations in a single-gene during DAP exposure raises concerns in an era of increasingly treatment-resistant infections. Lay summary: Daptomycin is an important antibiotic for fighting Staphylococcus infections. We identified variants in the WalK gene that were coincident with resistance in a clinical Staphylococcus epidermidis infection. Clinicians, hospital epidemiologists, and microbiology laboratories need to be aware of the potential for the evolution of drug resistance during prolonged daptomycin therapy.

Global Analysis of Human mRNA Folding Disruptions in Synonymous Variants Demonstrates Significant Population Constraint

ABSTRACTBackgroundIn most organisms the structure of an mRNA molecule is crucial in determining speed of translation, half-life, splicing propensities and final protein configuration. Synonymous variants which distort this wildtype mRNA structure may be pathogenic as a consequence. However, current clinical guidelines classify synonymous or “silent” single nucleotide variants (sSNVs) as largely benign unless a role in RNA splicing can be demonstrated.ResultsWe developed novel software to conduct a global transcriptome study in which RNA folding statistics were computed for 469 million SNVs in 45,800 transcripts using an Apache Spark implementation of ViennaRNA in the cloud. Focusing our analysis on the subset of 17.9 million sSNVs, we discover that variants predicted to disrupt mRNA structure have lower rates of incidence in the human population. Given that the community lacks tools to evaluate the potential pathogenic impact of sSNVs, we introduce a “Structural Predictivity Index” (SPI) to quantify this constraint due to mRNA structure.ConclusionsOur findings support the hypothesis that sSNVs may play a role in genetic disorders due to their effects on mRNA structure. Our RNA-folding scores provide a means of gauging the structural constraint operating on any sSNV in the human genome. Given that the majority of patients with rare or as yet to be diagnosed disease lack a molecular diagnosis, these scores have the potential to enable discovery of novel genetic etiologies. Our RNA Stability Pipeline as well as ViennaRNA structural metrics and SPI scores for all human synonymous variants can be downloaded from GitHub https://github.com/nch-igm/rna-stability.

Comparative Pharmacokinetics of Iophenoxic Acid in Cats and Brushtail Possums.

The comparative plasma pharmacokinetics of iophenoxic acid was studied in the cat and brushtail possum (Trichosurus vulpecula) to evaluate the suitability of this compound as a bait marker in these species. In cats, a mean peak plasma concentration of 946 micro g per 100 ml was obtained after administration of 1.5 mg/kg of iophenoxic acid. However, at the same dose level in possums, mean peak plasma concentration was only 157 micro g per 100 ml. Even after administration of 10 mg/kg of iophenoxic acid, the maximum peak plasma concentration in possums was only 459 micro g per 100 m/litre. The plasma elimination half-life for iophenoxic acid was 107 days in cats and close to one day in possums. Iophenoxic acid is therefore a suitable marker for cats but is unsuitable for use as a long-term or quantitative bait marker for possums. Differences between the possum and other mammals in gastrointestinal physiology and plasma protein configuration by account for the poor absorption and rapid elimination of iophenoxic acid in the possum.