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

Covert Sensitization Treatment with Alcoholics

An attempt was made to determine whether a behaviorally oriented conditioning approach, "covert sensitization," is more effective in the treatment of alcoholism than the commonly used problem-solving approach; and whether female counselors employing covert sensitization are more successful than males.A sample of 32 subjects selected on admission to Henwood Rehabilitation Centre, an in-patient facility of the Division of Alcoholism, in the Province of Alberta, was assigned to 2 treatment groups for the purpose of statistical comparison and evaluation.Eight staff counselors (4 males, 4 females) especially prepared in a 2-week, in-service workshop conduced covert sensitization with patients in treatment group 1 ; they also participated at least 50 percent of the time with other staff counselors in the problem-solving approach utilized in treatment group 2.A 3-month period of abstinence following discharge from Henwood was selected as the criterion measure in determining the results of treatment outcome. Appropriate statistical analysis of the criterion data yielded support for both the hypotheses tested