An Ice-Core-Based, Late Holocene History for the Transantarctic Mountains, Antarctica

Ice core records (major anions and cations, MSA, oxygen isotopes and particles) developed from two shallow (~200 m depth) sites in the Transantarctic Mountains provide documentation of much of the Holocene paleoenvironmental history of this region. From the more southerly site, Dominion Range, an ~7000-year-long record reveals change in the influence of tropospheric transport to the region. At this site, milder conditions and increased tropospheric inflow prior to ~1500 yr BP are characterized by increased seasalt (ss), terrestrial and marine biogenic inputs. Increased persistence and/or extent of polar stratospheric clouds accompanying generally cooler conditions characterize much of the period since ~1500 yr BP. From the more northerly site, Newall Glacier, the dramatic influence of the retreat of grounded ice from McMurdo Sound dated at[Denton et al., 1989] dominates much of the ice core record. This regional environmental change is documented by massive influxes to the core site of evaporitic salts from areas exposed during low lake level stands. During the past ~150 yr, both Dominion Range and Newall Glacier appear to be experiencing an overall increase in the exposure of ice-free terrain

Structural basis of DNA gyrase inhibition by antibacterial QPT-1, anticancer drug etoposide and moxifloxacin

New antibacterials are needed to tackle antibiotic-resistant bacteria. Type IIA topoisomerases (topo2As), the targets of fluoroquinolones, regulate DNA topology by creating transient double-strand DNA breaks. Here we report the first co-crystal structures of the antibacterial QPT-1 and the anticancer drug etoposide with Staphylococcus aureus DNA gyrase, showing binding at the same sites in the cleaved DNA as the fluoroquinolone moxifloxacin. Unlike moxifloxacin, QPT-1 and etoposide interact with conserved GyrB TOPRIM residues rationalizing why QPT-1 can overcome fluoroquinolone resistance. Our data show etoposide’s antibacterial activity is due to DNA gyrase inhibition and suggests other anticancer agents act similarly. Analysis of multiple DNA gyrase co-crystal structures, including asymmetric cleavage complexes, led to a ‘pair of swing-doors’ hypothesis in which the movement of one DNA segment regulates cleavage and religation of the second DNA duplex. This mechanism can explain QPT-1’s bacterial specificity. Structure-based strategies for developing topo2A antibacterials are suggested

Structure Guided Design and Synthesis of a Pyridazinone Series of Trypanosoma cruzi Proteasome Inhibitors

There is an urgent need for new treatments for Chagas disease, a parasitic infection which mostly impacts South and Central America. We previously reported on the discovery of GSK3494245/DDD01305143, a preclinical candidate for visceral leishmaniasis which acted through inhibition of the Leishmania proteasome. A related analogue, active against Trypanosoma cruzi, showed suboptimal efficacy in an animal model of Chagas disease, so alternative proteasome inhibitors were investigated. Screening a library of phenotypically active analogues against the T. cruzi proteasome identified an active, selective pyridazinone, the development of which is described herein. We obtained a cryo-EM co-structure of proteasome and a key inhibitor and used this to drive optimization of the compounds. Alongside this, optimization of the absorption, distribution, metabolism, and excretion (ADME) properties afforded a suitable compound for mouse efficacy studies. The outcome of these studies is discussed, alongside future plans to further understand the series and its potential to deliver a new treatment for Chagas disease.</p