The dearth of new medicines effective against antibiotic-resistant bacteria presents a growing global public health concern
. For more than five decades, the search for new antibiotics has relied ...heavily on the chemical modification of natural products (semisynthesis), a method ill-equipped to combat rapidly evolving resistance threats. Semisynthetic modifications are typically of limited scope within polyfunctional antibiotics, usually increase molecular weight, and seldom permit modifications of the underlying scaffold. When properly designed, fully synthetic routes can easily address these shortcomings
. Here we report the structure-guided design and component-based synthesis of a rigid oxepanoproline scaffold which, when linked to the aminooctose residue of clindamycin, produces an antibiotic of exceptional potency and spectrum of activity, which we name iboxamycin. Iboxamycin is effective against ESKAPE pathogens including strains expressing Erm and Cfr ribosomal RNA methyltransferase enzymes, products of genes that confer resistance to all clinically relevant antibiotics targeting the large ribosomal subunit, namely macrolides, lincosamides, phenicols, oxazolidinones, pleuromutilins and streptogramins. X-ray crystallographic studies of iboxamycin in complex with the native bacterial ribosome, as well as with the Erm-methylated ribosome, uncover the structural basis for this enhanced activity, including a displacement of the Formula: see text nucleotide upon antibiotic binding. Iboxamycin is orally bioavailable, safe and effective in treating both Gram-positive and Gram-negative bacterial infections in mice, attesting to the capacity for chemical synthesis to provide new antibiotics in an era of increasing resistance.
A transcriptional attenuation mechanism regulates expression of the bacterial tnaCAB operon. This mechanism requires ribosomal arrest induced by the regulatory nascent TnaC peptide in response to ...free L-tryptophan (L-Trp). In this study we demonstrate, using genetic and biochemical analyses, that in Escherichia coli, TnaC residue I19 and 23S rRNA nucleotide A2058 are essential for the ribosome's ability to sense free L-Trp. We show that the mutational change A2058U in 23S rRNA reduces the concentration dependence of L-Trp-mediated tna operon induction, whereas the TnaC I19L change suppresses this phenotype, restoring the sensitivity of the translating A2058U mutant ribosome to free L-Trp. These findings suggest that interactions between TnaC residue I19 and 23S rRNA nucleotide A2058 contribute to the creation of a regulatory L-Trp binding site within the translating ribosome.
Pregnant women and American Indian and Alaska Native people are at elevated risk of severe disease and mortality from 2009 pandemic influenza A/H1N1. We validated an electronic health record–based ...algorithm used by Indian Health Service to identify pregnant women in near real-time surveillance of pandemic influenza A/H1N1. We randomly selected a stratified sample of 515 patients at 3 Indian Health Service–funded hospitals with varied characteristics. With comprehensive review of patients' electronic health records as the gold standard, we calculated the positive predictive value and sensitivity of the pregnancy algorithm. The sensitivity of the algorithm at individual hospitals ranged from 94.1–96.0%. Positive predictive value ranged from 94.4–98.3%. Despite differences among hospitals on key characteristics, the pregnancy algorithm performed nearly equivalently with high positive predictive value and sensitivity at all facilities. It may prove helpful for surveillance during future epidemics and for targeting interventions for pregnant women and infants.
Recently, researchers at NASA Ames have defined a set of computational benchmarks designed to measure the performance of parallel supercomputers. The parallel implementation of the 5 kernel ...benchmarks from this suite on the IBM SP2, a scalable, distributed memory parallel computer is described. High-performance implementations of these kernels have been obtained by mapping the computation of these kernels to the underlying architecture of the SP2 machine. Performance results for the SP2 are compared with publicly available results for other high-performance computers.
The complexity of heat exchange mechanisms and difficulties in accurate determination of their coefficients make the thermal analysis a complicated problem at the beginning of the design process. In ...reality, only numerical calculations and specialized simulation programs can solve the systems of differential equations with very complicated boundary and initial conditions. The paper presents some aspects of describing of thermal model of the thick-film microcircuits with equivalent models (based on RC elements) which are used in temperature field simulation using PSPICE program
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