Bis-thiazolium salts constitute a new class of antihematozoan drugs that inhibit parasite phosphatidylcholine biosynthesis. They specifically accumulate in Plasmodium- and Babesia-infected red blood ...cells (IRBC). Here, we provide new insight into the choline analogue albitiazolium, which is currently being clinically tested against severe malaria. Concentration-dependent accumulation in P. falciparum-infected erythrocytes reached steady state after 90 to 120 min and was massive throughout the blood cycle, with cellular accumulation ratios of up to 1,000. This could not occur through a lysosomotropic effect, and the extent did not depend on the food vacuole pH, which was the case for the weak base chloroquine. Analysis of albitiazolium accumulation in P. falciparum IRBC revealed a high-affinity component that was restricted to mature stages and suppressed by pepstatin A treatment, and thus likely related to drug accumulation in the parasite food vacuole. Albitiazolium also accumulated in a second high-capacity component present throughout the blood cycle that was likely not related to the food vacuole and also observed with Babesia divergens-infected erythrocytes. Accumulation was strictly glucose dependent, drastically inhibited by H+/K+ and Na+ ionophores upon collapse of ionic gradients, and appeared to be energized by the proton-motive force across the erythrocyte plasma membrane, indicating the importance of transport steps for this permanently charged new type of antimalarial agent. This specific, massive, and irreversible accumulation allows albitiazolium to restrict its toxicity to hematozoa-infected erythrocytes. The intraparasitic compartmentation of albitiazolium corroborates a dual mechanism of action, which could make this new type of antimalarial agent resistant to parasite resistance.
Rising antimicrobial resistance challenges our ability to combat bacterial infections. The problem is acute for tuberculosis (TB), the leading cause of death from infection before COVID-19. Here, we ...developed a framework for multiple pharmaceutical companies to share proprietary information and compounds with multiple laboratories in the academic and government sectors for a broad examination of the ability of β-lactams to kill Mycobacterium tuberculosis (Mtb). In the TB Drug Accelerator (TBDA), a consortium organized by the Bill & Melinda Gates Foundation, individual pharmaceutical companies collaborate with academic screening laboratories. We developed a higher order consortium within the TBDA in which four pharmaceutical companies (GlaxoSmithKline, Sanofi, MSD, and Lilly) collectively collaborated with screeners at Weill Cornell Medicine, the Infectious Disease Research Institute (IDRI), and the National Institute of Allergy and Infectious Diseases (NIAID), pharmacologists at Rutgers University, and medicinal chemists at the University of North Carolina to screen ∼8900 β-lactams, predominantly cephalosporins, and characterize active compounds. In a striking contrast to historical expectation, 18% of β-lactams screened were active against Mtb, many without a β-lactamase inhibitor. One potent cephaloporin was active in Mtb-infected mice. The steps outlined here can serve as a blueprint for multiparty, intra- and intersector collaboration in the development of anti-infective agents.
Cet article propose une etude du role croissant que joue l'evaluation dans la gouvernance des services a domicile en Europe. L'introduction de quasi-marches dans plusieurs pays europeens va de pair ...avec un processus d'autonomisation de la fonction d'evaluation qui devient un veritable outil de regulation de la concurrence. Une analyse comparee des situations en Belgique, France et Royaume-Uni, tant de la demande que de l'offre de services, met en evidence les tensions recurrentes dans les objectifs de l'evaluation (qualite des services, maitrise des budgets sociaux, creation d'emploi), la faible prise en compte de la qualite de l'emploi ainsi que les limites des dispositifs standardises d'evaluation au regard de la rhetorique du libre choix de l'usager (consommateur). Reprinted by permission of Blackwell Publishers
RESUME**: Cet article propose une étude du rôle croissant que joue l’évaluation dans la gouvernance des services à domicile en Europe. L’introduction de quasi‐marchés dans plusieurs pays européens ...va de pair avec un processus d’autonomisation de la fonction d’évaluation qui devient un véritable outil de régulation de la concurrence. Une analyse comparée des situations en Belgique, France et Royaume‐Uni, tant de la demande que de l’offre de services, met en évidence les tensions récurrentes dans les objectifs de l’évaluation (qualité des services, maîtrise des budgets sociaux, création d’emploi), la faible prise en compte de la qualité de l’emploi ainsi que les limites des dispositifs standardisés d’évaluation au regard de la rhétorique du libre choix de l’usager (consommateur).
Cet article propose une étude du rôle croissant que joue l’évaluation dans la gouvernance des services à domicile en Europe. L’introduction de quasi-marchés dans plusieurs pays européens va de pair ...avec un processus d’autonomisation de la fonction d’évaluation qui devient un véritable outil de régulation de la concurrence. Une analyse comparée des situations en Belgique, France et Royaume-Uni, tant de la demande que de l’offre de services, met en évidence les tensions récurrentes dans les objectifs de l’évaluation (qualité des services, maîtrise des budgets sociaux, création d’emploi), la faible prise en compte de la qualité de l’emploi ainsi que les limites des dispositifs standardisés d’évaluation au regard de la rhétorique du libre choix de l’usager (consommateur);
Abstract
Im Folgenden beschreiben wir das aus dem Myxobakterium
Corallococcus coralloides
isolierte Antibiotikum Corramycin. Die lineare Peptidstruktur enthält eine bislang unbeschriebene (2
R
,3
S
...)‐γ‐
N
‐Methyl‐β‐hydroxyhistidin‐Einheit. Corramycin weist eine anti‐Gram‐negative Aktivität gegen
Escherichia coli
(
E. coli
) auf und wird über zwei Tansportersysteme, SbmA und YejABEF, in die Zelle aufgenommen. Darüber hinaus wurde das Corramycin Biosynthese‐Gencluster (BGC) identifiziert und ein Biosyntheseweg bestimmt, welcher auf einer 12‐modularen nicht‐ribosomale Peptidsynthetase/Polyketidsynthase beruht. Die bioinformatische Analyse des BGC in Verbindung mit der Entwicklung einer Totalsynthese ermöglichte die Aufklärung der absoluten Konfiguration des Moleküls. Außerdem führte die intravenöse Verabreichung von 20–30 mg Corramycin pro kg Mausgewicht in einem
E. coli
‐Infektionsmodell zu einer 100 %igen Überlebensrate der Tiere ohne toxische Nebenwirkungen. Somit ist Corramycin ein vielversprechender Ausgangspunkt für die Entwicklung eines wirksamen antibakteriellen Arzneimittels gegen Krankenhausinfektionen.
Im Folgenden beschreiben wir das aus dem Myxobakterium Corallococcus coralloides isolierte Antibiotikum Corramycin. Die lineare Peptidstruktur enthält eine bislang unbeschriebene ...(2R,3S)‐γ‐N‐Methyl‐β‐hydroxyhistidin‐Einheit. Corramycin weist eine anti‐Gram‐negative Aktivität gegen Escherichia coli (E. coli) auf und wird über zwei Tansportersysteme, SbmA und YejABEF, in die Zelle aufgenommen. Darüber hinaus wurde das Corramycin Biosynthese‐Gencluster (BGC) identifiziert und ein Biosyntheseweg bestimmt, welcher auf einer 12‐modularen nicht‐ribosomale Peptidsynthetase/Polyketidsynthase beruht. Die bioinformatische Analyse des BGC in Verbindung mit der Entwicklung einer Totalsynthese ermöglichte die Aufklärung der absoluten Konfiguration des Moleküls. Außerdem führte die intravenöse Verabreichung von 20–30 mg Corramycin pro kg Mausgewicht in einem E. coli‐Infektionsmodell zu einer 100 %igen Überlebensrate der Tiere ohne toxische Nebenwirkungen. Somit ist Corramycin ein vielversprechender Ausgangspunkt für die Entwicklung eines wirksamen antibakteriellen Arzneimittels gegen Krankenhausinfektionen.
Corramycin ist ein neuer Naturstoff, welcher von dem Myxobakterium Corallococcus coralloides produziert wird. Seine Struktur sowie die außergewöhnliche Total‐ und Biosynthese des Antibiotikums werden hier zum ersten Mal beschrieben. Corramycin zeigt keine Zytotoxizität und keine Kreuzresistenz mit gängigen Antibiotikaklassen. Des Weiteren ist die Wirkung von Corramycin in einem in vivo Sepsis Modell vielversprechend, was es zu einem Ausgangspunkt für ein neues Arzneimittel im Kampf gegen multiresistente Krankheitserreger macht.
Background
Septic shock patients exhibit an increased incidence of viral reactivation. Precise timing of such reactivation—as an early marker of immune suppression, or as a consequence of the ...later—is not known precisely. Here, using a fully designed nucleic acid extraction automated procedure together with tailored commercial PCR kits, we focused on the description of early reactivation within the first week of ICU admission of several herpes viruses and Torque Teno virus (TTV) in 98 septic shock patients.
Results
Most of septic shock patients had at least one viremia event during the first week (88%). TTV and herpesviruses were detected in 56% and 53% of septic shock patient, respectively. The two most frequent herpesviruses detected within the first week were EBV (35%) and HSV1 (26%). Different kinetic were observed among herpesviruses, faster for EBV and HSV1 than for CMV and HHV6. Although no association was found between herpes viremia and secondary infections, patients with herpesviridae-related viremia were more severe, e.g., higher SOFA scores and plasma lactate levels. While reactivating only 1 virus was not associated with mortality, patients with multiple viremia events had higher ICU mortality. Surprisingly, EBV + TTV early reactivation seemed associated with a lower D28 mortality. No clear association was observed between viremia and immune biomarkers.
Conclusion
Applying a semi-automated process of viral DNAemia determination to this cohort of 98 patients with septic shock, we observed that the number of patients with positive viremia increased during the first week in the ICU. Of note, there was no improvement in predicting the outcome when using viremia status. Nevertheless, this pilot study, introducing standardized procedures from extraction to detection, provides the basis for future standardized diagnostic criteria. A prospective longitudinal clinical study using these procedures will enable determination of whether such viremia is due to a lack of a latent virus control by the immune system or a true clinical viral infection.
A new therapeutic approach to malaria led to the discovery of ferroquine (FQ, SR97276). To assess the importance of the linkage of the ferrocenyl group to a 4-aminoquinoline scaffold, two series of ...4-aminoquinolines, structurally related to FQ, were synthesized. Evaluation of antimalarial activity, physicochemical parameters, and the β-hematin inhibition property indicate that the ferrocene moiety has to be covalently flanked by a 4-aminoquinoline and an alkylamine. Current data reinforced our choice of FQ as a drug candidate.
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