Molecular basis of fosmidomycin's action on the human malaria parasite Plasmodium falciparum

The human malaria parasite Plasmodium falciparum is responsible for the deaths of more than a million people each year. Fosmidomycin has been proven to be efficient in the treatment of P. falciparum malaria by inhibiting 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR), an enzyme of the non-mevalonate pathway, which is absent in humans. However, the structural details of DXR inhibition by fosmidomycin in P. falciparum are unknown. Here, we report the crystal structures of fosmidomycin-bound complete quaternary complexes of PfDXR. Our study revealed that (i) an intrinsic flexibility of the PfDXR molecule accounts for an induced-fit movement to accommodate the bound inhibitor in the active site and (ii) a cis arrangement of the oxygen atoms of the hydroxamate group of the bound inhibitor is essential for tight binding of the inhibitor to the active site metal. We expect the present structures to be useful guides for the design of more effective antimalarial compounds

Fosmidomycin Uptake into Plasmodium and Babesia-Infected Erythrocytes Is Facilitated by Parasite-Induced New Permeability Pathways

., a mouse malaria parasite. and related parasites. Our data provide further evidence that parasite-induced new permeability pathways may be exploited as routes for drug delivery

The role of plant characteristics in the resistance of white cabbage to onion thrips: preliminary results

The onion thrips, Thrips tabaci Lindeman (Thysanoptera: Thripidae) has been recognized as a severe worldwide pest of white cabbage (Brassica oleracea L. convar. capitata provar. capitata Duch.) for almost three decades. Although the most effective control measure is the use of resistant varieties, little is known about the resistance mechanism(s) involved. In 2007, a study at Tordas, Hungary, was carried out with 6 varieties to confirm that antixenosis is at least partly responsible for the resistance against onion thrips. The number of adult thrips and their progeny was counted on the outer ten head leaves at one-third of the heading process.At the same time, the light reflectance of old and outer head leaves was measured. The onion thrips damage was also assessed at full maturity. Antixenosis was found to be responsible for the resistance of ‘Balashi’, ‘Bloktor’ and ‘Riana’ varieties, since the number of adults and offspring found on head leaves was significantly lower than that of ‘Green gem’, ‘Hurricane’ and ‘Quisto’. The resistant varieties (‘Balashi’, ‘Bloktor’ and ‘Riana’) similarly suffered significantly lower damage than the susceptible ones (‘Green gem’, ‘Hurricane’ and ‘Quisto’). The light reflectance spectra of all six varieties were almost identical in the case of the old leaves, but a difference was found between the susceptible and resistant varieties when the reflectance of the outer head-forming leaves was measured. Similarly, the colour of the old leaves was not greatly different, but that of the outer head-forming leaves was correlated to the number of thrips adults found in the cabbage heads

Crystalline amidocerium(IV) oxides and a side-on bridging dioxygen complex

Complexes [Ce(NR2)(3)] (1) or [Ce(NR ''(2))(3)] (2) were cerium(III) precursors to the X-ray characterised crystalline oligomeric oxygen-containing amidocerium(IV) compounds [{Ce(NR2)(2)(mu-O)}(n)] (3, n = 2; 4, n = 3), [{Ce(NR ''(2))(2)(mu-O)}(4)] (5), [{(R2N)(3)Ce}(2)(mu-OMOM)] (6, M = Na; 7, M = K), [{(R2N)(3)CeOCe(NR2)(2)}(2)(mu-OKOK)] (8), and [{Ce(NR2)(3)}(2)(mu-eta(2):eta(2)-O-2)]center dot 2C(n)H(2n+2) (9, n = 6; 9', n = 5) [R = SiMe3, NR ''(2) = TMP = NC(Me)(2)(CH2)(3)CMe2]. Each was isolated in low, or for 5 very low, yield. Except for 4, the oxidising agent was O-2 at -27 degrees C in hexane (3, 6, 7, 8, 9), pentane (9'), or toluene (5), and a co-reagent for the alkali metal bis(trimethylsilyl)amido(oxy)cerate(IV)s was NaNR2 (8) or KNR2 (7, 8). From 1 and an quivalent portion of 2,6-Bu-t(2)-benzoquinone after 5 weeks in pentane there was obtained the bis(amido)cyclotricer(IV)oxane 4. The NMR spectral solution chemical shifts for NR2 groups of 3, 4, and 6-9 were consistent with each sample being diamagnetic and hence a Ce(IV) species. A transient amidocerium(IV) superoxide Ce(NR2)(3)(eta(2)-O-2) (J), or its TMP analogue, is considered to be the common first-formed intermediate in each case, while 4 is believed to have arisen from the adventitious hydrolysis of [{Ce(NR2)(3)O}(2)((Bu2C6H2)-Bu-t-1,4)]

Pharmacokinetic and pharmacodynamic profile of empagliflozin, a sodium glucose co-transporter 2 inhibitor.

Empagliflozin is an orally active, potent and selective inhibitor of sodium glucose co-transporter 2 (SGLT2), currently in clinical development to improve glycaemic control in adults with type 2 diabetes mellitus (T2DM). SGLT2 inhibitors, including empagliflozin, are the first pharmacological class of antidiabetes agents to target the kidney in order to remove excess glucose from the body and, thus, offer new options for T2DM management. SGLT2 inhibitors exert their effects independently of insulin. Following single and multiple oral doses (0.5-800 mg), empagliflozin was rapidly absorbed and reached peak plasma concentrations after approximately 1.33-3.0 h, before showing a biphasic decline. The mean terminal half-life ranged from 5.6 to 13.1 h in single rising-dose studies, and from 10.3 to 18.8 h in multiple-dose studies. Following multiple oral doses, increases in exposure were dose-proportional and trough concentrations remained constant after day 6, indicating a steady state had been reached. Oral clearance at steady state was similar to corresponding single-dose values, suggesting linear pharmacokinetics with respect to time. No clinically relevant alterations in pharmacokinetics were observed in mild to severe hepatic impairment, or in mild to severe renal impairment and end-stage renal disease. Clinical studies did not reveal any relevant drug-drug interactions with several other drugs commonly prescribed to patients with T2DM, including warfarin. Urinary glucose excretion (UGE) rates were higher with empagliflozin versus placebo and increased with dose, but no relevant impact on 24-h urine volume was observed. Increased UGE resulted in proportional reductions in fasting plasma glucose and mean daily glucose concentrations