Discovery of Inhibitors of the Lipopolysaccharide Transporter MsbA: From a Screening Hit to Potent Wild-Type Gram-Negative Activity.

The dramatic increase in the prevalence of multi-drug resistant Gram-negative bacterial infections and the simultaneous lack of new classes of antibiotics is projected to result in approximately 10 million deaths per year by 2050. We report on efforts to target the Gram-negative ATP-binding cassette (ABC) transporter MsbA, an essential inner membrane protein that transports lipopolysaccharide from the inner leaflet to the periplasmic face of the inner membrane. We demonstrate the improvement of a high throughput screening hit into compounds with on-target single digit micromolar (µM) minimum inhibitory concentrations against wild-type uropathogenic Escherichia coli, Klebsiella pneumoniae, and Enterobacter cloacae. A 2.98 Å resolution X-ray crystal structure of MsbA complexed with an inhibitor revealed a novel mechanism for inhibition of an ABC transporter. The identification of a fully encapsulated membrane binding site in Gram-negative bacteria led to unique physicochemical property requirements for wild-type activity.

Preparation and pharmacokinetics in beagle dogs of ganershu sustained-release pellets.

BACKGROUND: The active ingredients of Ganershu compound recipe, which are effective for hepatitis treatment in liver protection and transaminase reduction. However, the active ingredients of Ganershu compound recipe are poor absorption, which conduct it has a low oral bioavailability. OBJECTIVE: We prepared Ganershu sustained-release pellets (GSPs) by fluidized-bed on central composite design-response surface methodology and increase its bioavailability in beagle dogs. MATERIALS AND METHODS: In this study, GSPs were successfully prepared. The Drug-loaded pellets and sustained-release coated were carried out in fluidized-bed machine. GSP was optimized for fitting release, roundness, and the overall desirability by central composite design-response surface methodology. RESULTS: To optimize cumulative release profile, the outermost ethyl cellulose coating layer and the hydroxypropyl methyl cellulose (HPMC) swelling layer were employed, which were respectively given coating levels in terms of weight gain of 22% and 6%, the concentration of HPMC is 4.5% (g/ml). The pharmacokinetics of Ganershu normal pellets (GNPs) and GSP was studied in beagle dogs after oral administration. The naringenin as an index, the area under the curve0-∞ of naringenin in GSP was 1.38 times greater than that of GNP. Meanwhile, Tmax of GSP was prolonged for about 74%. CONCLUSION: This study can clearly indicate that we enhanced the oral bioavailability of Ganershu by preparing the GSP, which had the sustained dissolution and improved the potential of it for clinical application.

Birth Registration in China: Practices, Problems and Policies.

Data from interviews with staff of government offices, relevant literature and national statistics are used to analyze laws, regulations, rules, policies and operational procedures concerning birth registration in China. The current status of and existing problems with birth registration, as well as the influences of delayed birth registration on children's rights and welfare are examined. Finally, barriers to birth registration in China are explored and strategies to improve the process of birth registration and to protect children's rights are proposed. The main findings are as follows: First, the rate of birth registration in China is low and in rural areas and for marginalized children, it is even lower. Second, the dual birth registration system and interference from the Population and Family Planning department cause serious administrative difficulties. Third, the serious problems surrounding birth registration in China are a result of interactions among the interests of different stakeholders, while most stakeholders are unaware of the dimensions of the problems. Strategies and policies to promote birth registration are discussed.