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Search indexed NASA NTRS and DOE OSTI research on propulsion, heat transfer, battery materials and energy systems. Follow report and document links to the original sources.

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At least 937 records · Page 52
All sourcesNASA NTRSDOE OSTI
DOE OSTI2018

The Structural and Functional Basis for Recurring Sulfa Drug Resistance Mutations in Staphylococcus aureus Dihydropteroate Synthase

Staphylococcal species are a leading cause of bacterial drug-resistant infections and associated mortality. One strategy to combat bacterial drug resistance is to revisit compromised targets, and to circumvent resistance mechanisms using structure-assisted drug discovery. The folate pathway is an ideal candidate for this approach. Antifolates target an essential metabolic pathway, and the necessary detailed structural information is now available for most enzymes in this pathway. Dihydropteroate synthase (DHPS) is the target of the sulfonamide class of drugs, and its well characterized mechanism facilitates detailed analyses of how drug resistance has evolved. Here, we surveyed clinical genetic sequencing data in S. aureus to distinguish natural amino acid variations in DHPS from those that are associated with sulfonamide resistance. Five mutations were identified, F17L, S18L, T51M, E208K, and KE257_dup. Their contribution to resistance and their cost to the catalytic properties of DHPS were evaluated using a combination of biochemical, biophysical and microbiological susceptibility studies. These studies show that F17L, S18L, and T51M directly lead to sulfonamide resistance while unexpectedly increasing susceptibility to trimethoprim, which targets the downstream enzyme dihydrofolate reductase. The secondary mutations E208K and KE257_dup restore trimethoprim susceptibility closer to wild-type levels while further increasing sulfonamide resistance. Structural studies reveal that these mutations appear to selectively disfavor the binding of the sulfonamides by sterically blocking an outer ring moiety that is not present in the substrate. This emphasizes that new inhibitors must be designed that strictly stay within the substrate volume in the context of the transition state.

59 BASIC BIOLOGICAL SCIENCES↗
DOE OSTI2019

The Aemulus Project. III. Emulation of the Galaxy Correlation Function

Using the N-body simulations of the Aemulus Project, we construct an emulator for the nonlinear clustering of galaxies in real and redshift space. We construct our model of galaxy bias using the halo occupation framework, accounting for possible velocity bias. The model includes 15 parameters, including both cosmological and galaxy bias parameters. We demonstrate that our emulator achieves ~1% precision at the scales of interest, 0.1 h -1 Mpc < r < 10 h -1 Mpc, and recovers the true cosmology when tested against independent simulations. Our primary parameters of interest are related to the growth rate of structure, f, and its degenerate combination, fσ 8 . Using this emulator, we show that the constraining power on these parameters monotonically increases as smaller scales are included in the analysis, all the way down to 0.1 h -1 Mpc. For a BOSS-like survey, the constraints on fσ 8 from r < 30 h -1 Mpc scales alone are nearly a factor of two tighter than those from the fiducial BOSS analysis of redshift-space clustering using perturbation theory at larger scales. The combination of real- and redshift-space clustering allows us to break the degeneracy between f and σ 8, yielding an 11% constraint on f alone for a BOSS-like analysis. The current Aemulus simulations limit this model to surveys of massive galaxies. Future simulations will allow this framework to be extended to all galaxy target types, including emission-line galaxies.

79 ASTRONOMY AND ASTROPHYSICS↗