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.

Selective delta opioid receptor agonists are promising potential therapeutic agents for the treatment of various types of pain conditions. A spirocyclic derivative was identified as a promising hit through screening. Subsequent lead optimization identified compound 20 (ADL5859) as a potent, selective, and orally bioavailable delta agonist. Compound 20 was selected as a clinical candidate for the treatment of pain.

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Selective, nonpeptidic delta opioid receptor agonists have been the subject of great interest as potential novel analgesic agents. The discoveries of BW373U86 (1) and SNC80 (2) contributed to the rapid expansion of research in this field. However, poor drug-like properties and low therapeutic indices have prevented clinical evaluation of these agents. Doses of 1 and 2 similar to those required for analgesic activity produce convulsions in rodents and nonhuman primates. Recently, we described a novel series of potent, selective, and orally bioavailable delta opioid receptor agonists. The lead derivative, ADL5859 (4), is currently in phase II proof-of-concept studies for the management of pain. Further structure activity relationship exploration has led to the discovery of ADL5747 (36), which is approximately 50-fold more potent than 4 in an animal model of inflammatory pain. On the basis of its favorable efficacy, safety, and pharmacokinetic profile, 36 was selected as a clinical candidate for the treatment of pain.

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Ratoon sugarcane plantlets in southern China have suffered a serious chlorosis problem in recent years. To reveal the causes of chlorosis, plant nutrition in chlorotic sugarcane plantlets and the role of manganese (Mn) in this condition were investigated. The study results showed that the pH of soils growing chlorotic plantlets ranged from 3.74 to 4.84. The symptoms of chlorosis were similar to those of iron (Fe) deficiency while the chlorotic and non-chlorotic plantlets contained similar amount of Fe. Chlorotic plantlets had 6.4-times more Mn in their leaf tissues compared to the control plants. There was a significantly positive correlation between Mn concentration in the leaves and the exchangeable Mn concentration in the soils. Moreover, leaf Mn concentration was related to both seasonal changes in leaf chlorophyll concentration and to the occurrence of chlorosis. Basal stalks of mature sugarcanes contained up to 564.36 mg·kg-1 DW Mn. Excess Mn in the parent stalks resulted in a depress of chlorophyll concentration in the leaves of sugarcanes as indicated by lower chlorophyll concentration in the leaves of plantlets emerged from basal stalks. Ratoon sugarcane plantlets were susceptible to chlorosis due to high Mn accumulation in their leaves (456.90–1626.95 mg·kg-1 DW), while in planted canes chlorosis did not occur because of low Mn accumulation (94.64–313.41mg·kg-1 DW). On the other hand, active Fe content in chlorotic plantlets (3.39 mg kg-1 FW) was only equivalent to 28.2% of the concentration found in the control. These results indicate that chlorosis in ratoon sugarcane plantlets results from excessive Mn accumulated in parent stalks of planted cane sugarcanes grown on excessive Mn acidic soils, while active Fe deficiency in plantlets may play a secondary role in the chlorosis.

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Abstract:The interaction between aqueous Fe(II) (Fe(II) aq ) and iron minerals is an important reaction of the iron cycle, and it plays a critical role in impacting the environmental behavior of heavy metals in soils. Metal substitution into iron (hydr)oxides has been reported to reduce Fe atom exchange rates between Fe(II) aq and metal-substituted iron (hydr)oxides and inhibit the recrystallization of iron (hydr)oxides. However, the environmental behaviors of the substituted metal during these processes remain unclear. In this study, Fe(II) aq -induced recrystallization of Cr-substituted goethite (Cr-goethite) was investigated, along with the sequential release behavior of substituted Cr(III). Results from a stable Fe isotopic tracer and Mössbauer characterization studies show that Fe atom exchange occurred between Fe(II) aq and structural Fe(III) (Fe(III) oxide ) in Cr-goethites, during which the Cr-goethites were recrystallized. The Cr substitution inhibited the rates of Fe atom exchange and Cr-goethite recrystallization. During the recrystallization of Cr-goethites induced by Fe(II) aq , Cr(III) was released from Cr-goethite. In addition, Cr-goethites with a higher level of Cr-substituted content released more Cr(III). The highest Fe atom exchange rate and the highest amount of released Cr(III) were observed at a pH of 7.5. Under reaction conditions involving a lower pH of 5.5 or a higher pH of 8.5, there were substantially lower rates of Fe atom exchange and Cr(III) release. This trend of Cr(III) release was similar with changes in Fe atom exchange, suggesting that Cr(III) release is driven by Fe atom exchange. The release and reincorporation of Cr(III) occurred simultaneously during the Fe(II) aq -induced recrystallization of Cr-goethites, especially during the late stage of the observed reactions. Our findings emphasize an important role for Fe(II) aq -induced recrystallization of iron minerals in changing soil metal characteristics, which is critical for the evaluation of soil metal activities, especially those in Fe-rich soils.