Mtb-Selective 5-Aminomethyl Oxazolidinone Prodrugs: Robust Potency and Potential Liabilities.

Linezolid is a drug with proven human antitubercular activity whose use is limited to highly drug-resistant patients because of its toxicity. This toxicity is related to its mechanism of action─linezolid inhibits protein synthesis in both bacteria and eukaryotic mitochondria. A highly selective and potent series of oxazolidinones, bearing a 5-aminomethyl moiety (in place of the typical 5-acetamidomethyl moiety of linezolid), was identified. Linezolid-resistant mutants were cross-resistant to these molecules but not vice versa. Resistance to the 5-aminomethyl molecules mapped to an N-acetyl transferase (Rv0133) and these mutants remained fully linezolid susceptible. Purified Rv0133 was shown to catalyze the transformation of the 5-aminomethyl oxazolidinones to their corresponding N-acetylated metabolites, and this transformation was also observed in live cells of Mycobacterium tuberculosis. Mammalian mitochondria, which lack an appropriate N-acetyltransferase to activate these prodrugs, were not susceptible to inhibition with the 5-aminomethyl analogues. Several compounds that were more potent than linezolid were taken into C3HeB/FeJ mice and were shown to be highly efficacious, and one of these (9) was additionally taken into marmosets and found to be highly active. Penetration of these 5-aminomethyl oxazolidinone prodrugs into caseum was excellent. Unfortunately, these compounds were rapidly converted into the corresponding 5-alcohols by mammalian metabolism which retained antimycobacterial activity but resulted in substantial mitotoxicity.

Soil Water Movement and Groundwater Recharge Under Different Land Uses in a Flood-Irrigated Area.

The water shortage in agriculture area in China requires to reduce the consumption of excessive water in flood irrigation. Therefore, the dynamics of soil water regime is needed to investigate and water-saving irrigation is necessary to alleviate water shortage. This study investigated the impact of flood irrigation on soil water movement and recharge to groundwater in the Yellow River irrigation area of Yinchuan Plain, China. Combining comprehensive field observation, stable isotopic techniques and water balance simulation, we described the soil water mechanism in vadose zone covered with bare soil in 2019 and planted with maize in 2020. The soil layers affected by precipitation infiltration and evaporation were mainly 0-50 cm, while the soil influenced by irrigation was the entire profile in the mode of piston flow. The maize root took up the soil water up to the depth of 100 cm during the tasseling period. The infiltration and capillary rise in 2020 were similar with those in 2019. However, the total deep percolation was 156.5 mm in 2020 which was about 50% of that in 2019 because of the maize root water uptake. The leakage of ditch water was the major recharge resource of groundwater for the fast water table rise. Precise irrigation is required to minimize deep percolation and leakage of ditch water and reduce excessive unproductive evapotranspiration. Therefore, understanding the soil water movement and groundwater recharge is critical for agricultural water management to improve irrigation efficiency and water use efficiency in arid regions.

Sources and hydrogeochemical processes of groundwater under multiple water source recharge condition.

Ecological water replenishment (EWR) is an essential approach for improving the quantity and quality of regional water. The Chaobai River is a major river in Beijing that is replenished with water from multiple sources, including reclaimed water (RW), the South-North Water Transfer Project (SNTP), reservoir discharge (RD). The effects of multiple water source recharge (MWSR) on groundwater quality remain unclear. In this study, hydrochemical ions, isotopes (δ2H-H2O, δ18O-H2O, δ15N-NO3-, and δ18O-NO3-), mixing stable isotope analysis in R (MixSIAR), and hydrogeochemical modeling were used to quantify the contributions and impacts of different water sources on groundwater and to propose a conceptual model. The results showed that during the period before reservoir discharge, RW and SNTP accounted for 38 %-41 % and 54 % of the groundwater in their corresponding recharge areas, respectively. The groundwater in the RW recharge area contained high levels of Na+ and Cl- leading to the precipitation of halite, and was the main factor for the spatial variation in groundwater hydrochemical components. The surface water changed from Na·K - Cl·SO4 type to Ca·Mg - HCO3 type which was similar to groundwater after reservoir discharge. RD accounted for 30 % of the groundwater; however, it did not change the hydrochemical type of groundwater. Dual nitrate stable isotopes and MixSIAR demonstrated that RW was the primary source of NO3- in groundwater, contributing up to 76-89 %, and reservoir discharge effectively reduced the contribution of RW. δ15N-NO3- or δ18O-NO3- in relation to NO3-N suggests that denitrification is the main biogeochemical process of nitrogen in groundwater, whereas water recharge from the SNTP and RD reduces denitrification and dilutes NO3-. This study provides insights into the impact of anthropogenically controlled ecological water replenishment from different water sources on groundwater and guides the reasonable allocation of water resources.

[Occurrence Characteristics of Microplastics in Baiyangdian Lake Water and Sediments].

In order to explore the occurrence characteristics of microplastics in the freshwater environment of Baiyangdian Lake in China, ten overlying water samples and ten sediment samples were collected in Baiyangdian Lake of Hebei Province in October 2021, and the abundance distribution, shape, particle size, and polymer type of microplastics in the samples were identified using laboratory pretreatment, microscope observation, and laser infrared spectroscopy. The sedimentation law of microplastics at the overlying water-sediment interface was studied using the Stokes sedimentation formula, and their pollution characteristics and potential sources were analyzed. The abundances of microplastics in the overlying water and sediments in Baiyangdian Lake ranged from 474-19382 n·m-3 and 95.3-29542.5 n·kg-1, respectively, with an average value of 6255.4 n·m-3 and 11088 n·kg-1. The main polymer of the microplastics in the overlying water was polyethylene terephthalate[PET, (17.20±0.26)%], and the microplastics in the sediments were mainly chlorinated polyethylene[CPE, (46.11±1.30)%]. The sedimentation velocities of microplastics in the sedimentation zone ranged from 0.0793-111.7547 mm·s-1. The particles with larger particle size had higher sedimentation velocity and easily settled and remained in the sediments. The main sources of microplastic pollution in the study area were the discharge of textile fibers from washing wastewater and the wear and tear of ship paint, ship rubber, and building materials.

[Spatial-temporal Variation in Water Quality and Its Response to Precipitation and Land Use in Baiyangdian Lake in the Early Stage of the Construction of Xiong'an New Area].

To assess the water quality of Baiyangdian Lake in the early stage of construction of the Xiong'an New Area, the water quality data in Baiyangdian Lake from December 2020 to November 2021 were collected from five typical monitoring stations. Using the remote-sensing interpretation of land use types, Pearson correlation analysis, comprehensive pollution index, and principal component analysis, the spatial-temporal variation characteristics of the water quality and its response to precipitation and land use structure at different spatial scales were explored in Baiyangdian Lake. The results showed that:① the water quality of Baiyangdian Lake was the best in spring and the worst in summer. Nutrient pollution was the heaviest at Nanliuzhuang, which was greatly affected by the Fuhe River. Organic pollution was the heaviest at Caiputai. ② The comprehensive pollution index of Nanliuzhuang was the highest, followed by that of Shaochedian, Guangdianzhangzhuang, Caiputai, and Quantou. The main excessive pollutant was TN, and the pollution index of 1.55 reached the level of severe pollution. The water quality of Baiyangdian Lake was significantly better than that before the construction of the Xiong'an New Area. ③ The construction land and cropland within the 1.5 km buffer zone had the greatest impact on turbidity, NH4+-N, and TP. While the reed wetland acted as the "sink" for intercepting and absorbing pollutants, it also released nitrogen into the 800 m buffer zone, which was the "source" of the pollutants. ④ The correlation between water quality indicators and land use structure in the rainy season was lower than that in the dry season. This was due to the dilution effect of the upstream reservoir discharging in the rainy season, which weakened the impact of pollutants in the rainfall runoff on the water quality of Baiyangdian Lake.

Identifying surface water and groundwater interactions using multiple experimental methods in the riparian zone of the polluted and disturbed Shaying River, China.

Identifying groundwater (GW)-surface water (SW) interactions in riparian zones is important for assessing the transport pathways of pollutants and all potential biochemical processes, particularly in rivers with artificially controlled water levels. In this study, we constructed two monitoring transects along the nitrogen-polluted Shaying River, China. The GW-SW interactions were qualitatively and quantitatively characterized through an intensive 2-y monitoring program. The monitoring indices included water level, hydrochemical parameters, isotopes (δ18O, δD, and 222Rn) and microbial community structures. The results showed that the sluice altered the GW-SW interactions in the riparian zone. A decrease in river level occurs during the flood season owing to sluice regulation, resulting in discharge of riparian GW into the river. The water level, hydrochemistry, isotopes, and microbial community structures in near-river wells were similar to those in the river, indicating mixing of the river water with the riparian GW. As the distance from the river increased, the percentage of river water in the riparian GW decreased, whereas the GW residence time increased. We found that nitrogen may be easily transported through the GW-SW interactions, acting as a sluice regulator. Nitrogen stored in river water may be removed or diluted by mixing GW and rainwater during the flood season. As the residence time of the infiltrated river in the riparian aquifer increased, nitrate removal increased. Identifying the GW-SW interactions is crucial for water resource regulation and for further tracing the transport of contaminants such as nitrogen in the historically polluted Shaying River.

[Impact of Maximum Precipitation in 2017 on the Runoff Component of Reclaimed Water-Intaking River].

The hydrology of rivers recharged with reclaimed water is an important factor controlling its aquatic environment and biochemical processes, which change during the wet season. To understand the impacts of precipitation on hydrological conditions, water samples were collected from seven sites in three periods (before the wet season and during and after the maximum precipitation in July 2017, with 3.3 return periods) throughout a reclaimed water intake area of the Chaobai River in the Shunyi District, Beijing. The hydrogen-oxygen isotope characteristics and chloride content were measured. The results show that the hydrogen and oxygen isotopes of precipitation are mainly affected by the amount of the effect. The minor variation in the later period is due to changes in the sources of moisture. Within three days after precipitation, the slope runoff continues and the fraction of each section varies greatly. The reclaimed water reaches the downstream section through the preferred pathway. The water component ratio of the slope runoff increases from 2% to 85.6% in the direction of the flow, while the reclaimed water ratio decreases from 90% to 67%. The stream remains effluent from sections SY01 to SY05 that are recharged by the slope runoff, reclaimed water, and in-site river water, while the sections SY06 to SY07 are mainly recharged by the slope runoff and in-site river water within three days after the precipitation (the stream effluent is unremarkable).

Impacting Global Health Through Equipment Repurposing: Measurable Progress Through the Accumulation of Many Tiny Victories.

There is an active and growing effort occurring in laboratories throughout Africa to research the underpinnings of endemic communicable diseases, many of which are considered "neglected tropical diseases" as defined by the World Health Organization. Across the continent, scientists, doctors, health care workers, and students investigate the in vitro activity of pharmacologically active extracts against known pathogens in hope of discovering new treatments for the diseases that affect the local population. During the summer of 2014, I had the opportunity to visit laboratories in 3 different countries engaged in this area of research through participation in the Merck Fellowship for Global Health (Merck is known as Merck, Sharp & Dohme outside of the United States and Canada.), in which Merck sponsors employees on a short-term sabbatical to work with a global health-focused nonprofit organization. This commentary describes the objectives of the fellowship program, the specific project to which my co-fellow and I contributed, and the story of a subsequent equipment donation effort that was inspired by my individual fellowship experience. It also captures a few of the more notable challenges and opportunities for the scientists in the laboratories we visited. Finally, for the reader who may be curious as to how she or he can contribute, I hope to move you to action by highlighting some of the opportunities for researchers to positively and creatively impact global health from their "home" lab benches and hoods.

Linking High-Throughput Screens to Identify MoAs and Novel Inhibitors of Mycobacterium tuberculosis Dihydrofolate Reductase.

Though phenotypic and target-based high-throughput screening approaches have been employed to discover new antibiotics, the identification of promising therapeutic candidates remains challenging. Each approach provides different information, and understanding their results can provide hypotheses for a mechanism of action (MoA) and reveal actionable chemical matter. Here, we describe a framework for identifying efficacy targets of bioactive compounds. High throughput biophysical profiling against a broad range of targets coupled with machine learning was employed to identify chemical features with predicted efficacy targets for a given phenotypic screen. We validate the approach on data from a set of 55 000 compounds in 24 historical internal antibacterial phenotypic screens and 636 bacterial targets screened in high-throughput biophysical binding assays. Models were built to reveal the relationships between phenotype, target, and chemotype, which recapitulated mechanisms for known antibacterials. We also prospectively identified novel inhibitors of dihydrofolate reductase with nanomolar antibacterial efficacy against Mycobacterium tuberculosis. Molecular modeling provided structural insight into target-ligand interactions underlying selective killing activity toward mycobacteria over human cells.

Discovery of a potent and selective ROMK inhibitor with improved pharmacokinetic properties based on an octahydropyrazino[2,1-c][1,4]oxazine scaffold.

Following the discovery of small molecule acyl piperazine ROMK inhibitors, the acyl octahydropyrazino[2,1-c][1,4]oxazine series was identified. This series displays improved ROMK/hERG selectivity, and as a consequence, the resulting ROMK inhibitors do not evoke QTc prolongation in an in vivo cardiovascular dog model. Further efforts in this series led to the discovery of analogs with improved pharmacokinetic profiles. This new series also retained comparable ROMK potency compared to earlier leads.