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To address the emergence of SARS-CoV-2, multiple clinical trials in humans were rapidly started, including those involving an oral treatment by nitazoxanide, despite no or limited pre-clinical evidence of antiviral efficacy.In this work, we present a complete pre-clinical evaluation of the antiviral activity of nitazoxanide against SARS-CoV-2.First, we confirmed the in vitro efficacy of nitazoxanide and tizoxanide (its active metabolite) against SARS-CoV-2. Then, we demonstrated nitazoxanide activity in a reconstructed bronchial human airway epithelium model. In a SARS-CoV-2 virus challenge model in hamsters, oral and intranasal treatment with nitazoxanide failed to impair viral replication in commonly affected organs. We hypothesized that this could be due to insufficient diffusion of the drug into organs of interest. Indeed, our pharmacokinetic study confirmed that concentrations of tizoxanide in organs of interest were always below the in vitro ECThese preclinical results suggest, if directly applicable to humans, that the standard formulation and dosage of nitazoxanide is not effective in providing antiviral therapy for Covid-19.This work was supported by the Fondation de France "call FLASH COVID-19", project TAMAC, by "Institut national de la santé et de la recherche médicale" through the REACTing (REsearch and ACTion targeting emerging infectious diseases), by REACTING/ANRS MIE under the agreement No. 21180 ('Activité des molécules antivirales dans le modèle hamster'), by European Virus Archive Global (EVA 213 GLOBAL) funded by the European Union's Horizon 2020 research and innovation program under grant agreement No. 871029 and DNDi under support by the Wellcome Trust Grant ref: 222489/Z/21/Z through the COVID-19 Therapeutics Accelerator".

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.

Herein, we describe the myxobacterial natural product Corramycin isolated from Corallococcus coralloides. The linear peptide structure contains an unprecedented (2R,3S)-γ-N-methyl-β-hydroxy-histidine moiety. Corramycin exhibits anti-Gram-negative activity against Escherichia coli (E. coli) and is taken up via two transporter systems, SbmA and YejABEF. Furthermore, the Corramycin biosynthetic gene cluster (BGC) was identified and a biosynthesis model was proposed involving a 12-modular non-ribosomal peptide synthetase/polyketide synthase. Bioinformatic analysis of the BGC combined with the development of a total synthesis route allowed for the elucidation of the molecule's absolute configuration. Importantly, intravenous administration of 20 mg kg

Herein, we describe the myxobacterial natural product Corramycin (1) isolated from Corallococcus coralloides (C. coralloides). Corramycin is a linear peptide containing an unprecedented (2R,3S)  N-methyl-β-hydroxy histidine moiety and exhibiting anti-Gram-negative activity against Escherichia coli. Moreover, we describe the Corramycin biosynthetic gene cluster (BGC) and propose a biosynthesis model involving a 12-modular non-ribosomal peptide synthetase (NRPS)/polyketide synthase (PKS). Bioinformatic analysis of the BGC combined with the development of a total synthesis route allowed for the elucidation of the molecule’s absolute configuration. Furthermore, we show that the uptake of Corramycin in E. coli depends on two transporter systems, SbmA and YejABEF. Importantly, intravenous administration of 30 mg kg 1 of Corramycin in an E. coli mouse infection model resulted in significantly reduced colony forming units (CFU) and in 60 % survival of animals, with no toxic effects observed in vitro or in vivo. Corramycin is thus an intriguing innovative starting point to develop a potent antibacterial drug against hospital acquired infections.

Public-Owned Enterprises (POEs) are generally large economic enterprises owned and governed by state institutions. POEs generally are the sole or the main provider of the key public goods and services as water, electricity, transport, telecommunications, and postal services. If administered efficiently, the POEs are important for national development and perspective of natural economic resources. The concern is how accurately these monopolistic enterprises are organized in aspects of administrative and managerial perspectives to function as effectively as possible for the objectives they are created. Therefore an overall summary of the public-owned enterprises is presented through their process of emerging, privatization, and evolution in Albania, southeast Europe. The process was accompanied by shortcomings due to its ad-hoc nature; and associated with negative effects of bad management, governance corruption, and low efficiency of the operational activities and results.

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.

An ever-increasing demand for novel antimicrobials to treat life-threatening infections caused by the global spread of multidrug-resistant bacterial pathogens stands in stark contrast to the current level of investment in their development, particularly in the fields of natural-product-derived and synthetic small molecules. New agents displaying innovative chemistry and modes of action are desperately needed worldwide to tackle the public health menace posed by antimicrobial resistance. Here, our consortium presents a strategic blueprint to substantially improve our ability to discover and develop new antibiotics. We propose both short-term and long-term solutions to overcome the most urgent limitations in the various sectors of research and funding, aiming to bridge the gap between academic, industrial and political stakeholders, and to unite interdisciplinary expertise in order to efficiently fuel the translational pipeline for the benefit of future generations., Antimicrobial resistance is an increasing threat to public health and encouraging the development of new antimicrobials is one of the most important ways to address the problem. This Roadmap article aims to bring together industrial, academic and political partners, and proposes both short-term and long-term solutions to this challenge.

Cet article interroge les recompositions de l’intervention sociale territoriale ou territorialisee a partir de l’analyse de dispositifs mettant en place des formes d’accompagnement global pour des publics dont les besoins, identifies comme complexes, sont reputes necessiter une approche transversale, mobilisant plusieurs secteurs d’intervention. Il s’appuie sur une enquete a caractere monographique portant sur des dispositifs destines a trois categories de publics : personnes âgees dependantes, demandeurs d’emploi en difficulte d’insertion et meres isolees precaires. L’article examine ces dispositifs en soulignant leur caractere souvent multiniveau ainsi que la variete des modeles de transversalite dont ils relevent. Il analyse ensuite les difficultes de leur mise en œuvre, en montrant que ces dispositifs transversaux interrogent les competences territoriales, la geographie des interventions aupres des publics et les competences professionnelles des acteurs. Enfin, il explore les defis que pose leur gouvernance.

The emergence and spread of Plasmodium falciparum resistance to first-line antimalarials creates an imperative to identify and develop potent preclinical candidates with distinct modes of action. Here, we report the identification of MMV688533, an acylguanidine that was developed following a whole-cell screen with compounds known to hit high-value targets in human cells. MMV688533 displays fast parasite clearance in vitro and is not cross-resistant with known antimalarials. In a P. falciparum NSG mouse model, MMV688533 displays a long-lasting pharmacokinetic profile and excellent safety. Selection studies reveal a low propensity for resistance, with modest loss of potency mediated by point mutations in PfACG1 and PfEHD. These proteins are implicated in intracellular trafficking, lipid utilization, and endocytosis, suggesting interference with these pathways as a potential mode of action. This preclinical candidate may offer the potential for a single low-dose cure for malaria.

Background & Aims Covalently closed circular DNA (cccDNA) is the episomal form of the HBV genome that stably resides in the nucleus of infected hepatocytes. cccDNA is the template for the transcription of 6 major viral RNAs, i.e. preC, pg, preS1/2, S and HBx RNA. All viral transcripts share the same 3' end and are all to various degrees subsets of each other. Especially under infection conditions, it has been difficult to study in depth the transcription of the different viral transcripts. We thus wanted to develop a method with which we could easily detect the full spectrum of viral RNAs in any lab. Methods We set up an HBV full-length 5'RACE (rapid amplification of cDNA ends) method with which we measured and characterized the full spectrum of viral RNAs in cell culture and in chronically infected patients. Results In addition to canonical HBx transcripts coding for full-length X, we identified shorter HBx transcripts potentially coding for short X proteins. We showed that interferon-β treatment leads to a strong reduction of preC and pgRNAs but has only a moderate effect on the other viral transcripts. We found pgRNA, 1 spliced pgRNA variant and a variety of HBx transcripts associated with viral particles generated by HepAD38 cells. The different HBx RNAs are both capped and uncapped. Lastly, we identified 3 major categories of circulating RNA species in patients with chronic HBV infection: pgRNA, spliced pgRNA variants and HBx. Conclusions This HBV full-length 5'RACE method should significantly contribute to the understanding of HBV transcription during the course of infection and therapy and may guide the development of novel therapies aimed at targeting cccDNA. Lay summary Especially under infection conditions, it has been difficult to study the different hepatitis B virus transcripts in depth. This study introduces a new method that can be used in any standard lab to discriminate all hepatitis B viral transcripts in cell culture and in the serum of patients.

Vaccines prevent infectious diseases, but vaccination is not without risk and adverse events are reported although they are more commonly reported for biologicals than for vaccines. Vaccines and biologicals must undergo vigorous assessment before and after licensure to minimise safety concerns. Potential safety concerns should be identified as early as possible during the development for vaccines and biologicals to minimize investment risk. State-of-the art tools and methods to identify safety concerns and biomarkers that are predictive of clinical outcomes are indispensable. For vaccines and adjuvant formulations, systems biology approaches, supported by single-cell microfluidics applied to translational studies between preclinical and clinical studies, could improve reactogenicity and safety predictions. Next-generation animal models for clinical assessment of injection-site reactions with greater relevance for target human population and criteria to define the level of acceptability of local reactogenicity at vaccine injection sites in pre-clinical animal species should be assessed. Advanced in silico machine-learning-based analytics, species-specific cell or tissue expression, receptor occupancy and kinetics and cell-based assays for functional activity are needed to improve pre-clinical safety assessment of biologicals. The in vitro MIMIC® system could be used to compliment preclinical and clinical studies for assessing immune-toxicity, immunogenicity, immuno-inflammatory and mode of action of biologicals and vaccines. Sanofi Pasteur brought together leading experts in this field to review the state-of-the-art at a unique 'Safety Biomarkers Symposium' on 28-29 November 2017. Here we summarise the proceedings of this symposium. This unique scientific meeting confirmed the importance for institutions and industrial organizations to collaborate to develop tools and methods needed for predicting reactogenicity and immune-inflammatory reactions to vaccines and biologicals, and to develop more accuracy, reliability safety biomarkers, to inform decisions on the attrition or advancement of vaccines and biologicals.

Les politiques locales de l'économie sociale et solidaire (ESS) constituent un nouveau domaine de l'action publique en France. Les élus comme les représentants de l'ESS revendiquent publiquement le terme de co-construction pour qualifier leur processus d'élaboration, voire de leur mise en œuvre. Cette participation ouverte et organisée d’une pluralité d’acteurs de la société civile à la conception, au suivi et à l’évaluation des politiques publiques s'explique autant par la volonté de faire de la politique autrement que par des considérations pragmatiques. Cet article analyse les différentes configurations de cette co-construction des politiques locales de l'ESS en soulignant les potentialités et les limites de processus situés au croisement de démocraties représentative et participative. Local public policies in favour of social and solidarity-based economy (SSE) are a new field public action in France. Local elected officials as the actors of SSE publicly advocate the notion of co-construction in order to stress the processes of policy-making and implementation. This opened and organised participation of various members of civil society to the formulation, monitoring and assessment of local public policies can be explained by the willingness of doing politics differently as much as pragmatic considerations. This article analyses different configurations of such co-construction of SSE local policies underlining the contributions and limits of process placed between representative and participative democracies.

Issus d’une démarche collaborative et expérimentale entre acteurs, réseaux et chercheurs de l’ESS, les pôles territoriaux de coopération économique (PTCE) ont connu un processus rapide d’institutionnalisation. Le retour sur les étapes clés de cette histoire et le repérage des raisons de cette mise à l’agenda politique permettent d’éclairer les enjeux relatifs à la qualification en tant que PTCE de tel ou tel regroupement coopératif multiacteurs. Dans ce contexte, une caractérisation empirique de la morphologie, des modalités de coopération et de la gouvernance de plusieurs PTCE est nécessaire pour souligner les potentiels et la diversité de ces expérimentations en mettant à distance des cadrages juridiques et politiques parfois trop normatifs ou restrictifs., The fruit of a joint experimental project among SSE organisations, networks and researchers, regional economic cooperation clusters (pôles territoriaux de coopération économique, PTCEs) have been undergoing rapid institutionalisation. To understand the issues involved in determining which cooperative groupings can be called PTCEs, the article looks back at the key stages in this development and how it appeared on the political agenda. In this context, an empirical description of the morphology, forms of cooperation and governance of several PTCEs is needed to highlight the potential and diversity of these experiments, putting aside legal and political frameworks which are sometimes too normative and restrictive., Resultando de un enfoque de colaboración y de experimentación entre actores, redes e investigadores de la ESS, los polos territoriales de cooperación económica (PTCE) han conocido un proceso rápido de institucionalización. Una vuelta a las etapas clave de esta historia y la identificación de los motivos de esta incorporación en la agenda política permiten aclarar los retos relativos a la calificación como PTCE de una agrupación cooperativa multi-actores determinada. En este contexto, una caracterización empírica de la morfología, de las modalidades de cooperación y de la gobernanza de varios PTCE, parece necesaria para destacar los potenciales y la diversidad de estos experimentos, manteniendo a distancia los marcos jurídicos y políticos que a veces son demasiado normativos o restrictivos.

INTRODUCTION Mycobacterium tuberculosis (Mtb) is the leading global cause of lethal infection in humans and accounts for the largest number of drug-resistant infections by a single bacterial pathogen. Resistance is particularly high against the most widely prescribed tuberculosis (TB) drug, isoniazid. Isoniazid blocks synthesis of mycolates, ultralong-chain fatty acids that provide structure to the waxy coat that surrounds Mtb cells and are incorporated into some of its virulence lipids. There is currently no known method to block the synthesis of both mycolates and nonmycolate-containing virulence lipids of Mtb at a single point of control. One such control point is phosphopantetheinyl transferase (PptT). PptT transfers 4′-phosphopantetheine (Ppt) from coenzyme A (CoA) to acyl carrier proteins (ACPs) that synthesize the lipids critical to Mtb structural integrity and virulence. RATIONALE TB drug discovery often begins with whole-cell, high-throughput screens that yield compounds that kill Mtb by unknown means. Selection of Mtb mutants resistant to these compounds can indicate candidate targets of the active compound, but experimental validation is required to confirm the functionally relevant target, which is often an enzyme. A suitable target must be essential in vivo, such that its inhibition precludes development of TB in animal models, but also “vulnerable,” meaning that a pharmacologically attainable level of inhibition should be lethal to Mtb within a patient. The inhibitor should act only on Mtb, and resistance should be rare. RESULTS Screening a chemical library revealed an amidino-urea compound called “8918” that kills Mtb, including drug-resistant clinical isolates. 8918 inhibits Mtb in mice and spares other bacteria, yeast, and mammalian cells. Rare Mtb mutants resistant to 8918 bore a point mutation in the PptT gene rv2794c, altering an amino acid residue overlying the Ppt-binding pocket of PptT. When Mtb carried the mutant allele as an extra copy of rv2794c, the Mtb was protected from 8918. 8918 inhibited recombinant PptT, albeit noncompetitively and incompletely. The impact of 8918 on the Mtb metabolome and lipids was consistent with inhibition of PptT in the intact cell. A crystal structure of the PptT-8918 complex at 1.8-Å resolution confirmed that 8918 binds within the Ppt binding pocket, adjacent to the phosphoadenosine phosphate portion of CoA. Intact CoA remained in the PptT-8918 complex, but the Ppt arm was displaced, decreasing but not abolishing PptT’s catalytic activity. Strains of Mtb producing reduced amounts of PptT became hypersensitive to 8918. It was puzzling that even partial inhibition of PptT killed Mtb. We observed that mutants with disruption of rv2795c, a gene encoding a hypothetical protein, were also highly resistant to 8918. Recombinant Rv2795c protein hydrolyzed Ppt from a mycolate-building holo-ACP that is a substrate for PptT. The action of this Ppt hydrolase (PptH) resembled that of nonhomologous enzymes called ACP hydrolases that remove Ppt from ACPs in vitro but whose physiological function is unknown. CONCLUSION We identified a small molecule that kills Mtb by inhibiting PptT, demonstrating that a key enzyme in CoA metabolism is a viable target for TB drug development. Even partial inhibition of PptT is toxic to Mtb, likely because PptH synergizes with the inhibitor by undoing the PptT reaction. PptT and PptH are co-regulated by translation from the same operon, and thus Mtb cannot respond to inhibition of PptT by making more PptT without also generating more PptH. The joint functioning of PptT and PptH suggests that Mtb closely regulates the activation of ACPs. The transcriptional co-regulation and constitutive function of both members of the PptT-PptH couple suggests that a posttranslational signal that impairs PptT more than PptH could allow Mtb to rapidly reverse a prior commitment to synthesis of its metabolically most costly lipids.

Coordinated action and social rehabilitation “crèches”. Two cross-sector initiatives for the rehabilitation of vulnerable single mothers. Having underscored the relevance today of the social rehabilitation of vulnerable single mothers, the article analyses two cross-sector initiatives designed to combine access to job support for these mothers with care for their child(ren). The first is to develop coordinated action between existing facilities for childcare and social rehabilitation, while the second involves the creation of a “ crèche” for association-based rehabilitation. While these two cross-sector initiatives have enjoyed a certain amount of success in the region concerned, their implementation, which requires partnerships between professionals from different sectors, has proven delicate. Examining their rollout allows us to highlight the importance of their economic model and the role of the intermediaries at their disposal (or not) at various levels., Après avoir rappelé l’actualité de la question de l’insertion des mères de familles monoparentales précaires, cet article analyse deux dispositifs transversaux d’insertion visant à coupler l’accès de ces mères à un accompagnement vers l’emploi et à un mode d’accueil pour leur(s) enfant(s). Le premier construit un parcours coordonné entre des services existants d’accueil de la petite enfance et d’insertion, tandis que le second consiste en la création d’une crèche d’insertion associative. Si ces deux dispositifs transversaux rencontrent un certain succès dans leur territoire, leur mise en place, qui mobilise des partenariats entre des professionnels de secteurs différents, se révèle délicate. L’examen de leur déploiement permet de mettre en évidence l’importance de leur modèle économique et le rôle des relais dont ils disposent (ou non) à différents niveaux., Bucolo Elisabetta, Eydoux Anne, Fraisse Laurent. Parcours coordonné et crèche d’insertion. Deux dispositifs transversaux d’insertion des mères de familles monoparentales précaires. In: Revue des politiques sociales et familiales, n°127, 2018. Dossier « Vivre la monoparentalité en situation de précarité ». pp. 37-48.

New for old—TB drug development Tuberculosis (TB) is a global health threat for which there is only lengthy drug treatment. Patients need to consume multiple tablets over several months and frequently fail to complete their treatment. Consequently, drug-resistant strains of the pathogen have emerged, which add to the threat. Kling et al. revisited a natural product called griselimycin, extracted from the same organism that produced the prototype anti-TB drug, streptomycin. Unmodified griselimycin has poor pharmacological properties. However, one synthetic derivative had improved oral uptake and penetrated cells of the immune system that harbor the TB mycobacterium. In combination with other drugs, the griselimycin derivative showed high potency in mice with TB. Science , this issue p. 1106

Albitiazolium is the lead compound of bisthiazolium choline analogues and exerts powerful in vitro and in vivo antimalarial activities. Here we provide new insight into the fate of albitiazolium in vivo in mice and how it exerts its pharmacological activity. We show that the drug exhibits rapid and potent activity and has very favorable pharmacokinetic and pharmacodynamic properties. Pharmacokinetic studies in Plasmodium vinckei-infected mice indicated that albitiazolium rapidly and specifically accumulates to a great extent (cellular accumulation ratio, >150) in infected erythrocytes. Unexpectedly, plasma concentrations and the area under concentration-time curves increased by 15% and 69% when mice were infected at 0.9% and 8.9% parasitemia, respectively. Albitiazolium that had accumulated in infected erythrocytes and in the spleen was released into the plasma, where it was then available for another round of pharmacological activity. This recycling of the accumulated drug, after the rupture of the infected erythrocytes, likely extends its pharmacological effect. We also established a new viability assay in the P. vinckei-infected mouse model to discriminate between fast- and slow-acting antimalarials. We found that albitiazolium impaired parasite viability in less than 6 and 3 h at the ring and late stages, respectively, while parasite morphology was affected more belatedly. This highlights that viability and morphology are two parameters that can be differentially affected by a drug treatment, an element that should be taken into account when screening new antimalarial drugs.

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.

International audience

This chapter analyses how a historical local dispute in a renewal operation has led to an emblematic housing innovation called Ilot Stephenson at the periphery of one of the biggest urban renewal projects in the Roubaix-Tourcoing-Wattrelot district. A protest by inhabitants against the demolition of popular housing led to co-production between architects, local authorities and inhabitants. Access to homes at reduced cost has been achieved thanks to an innovative mode of architectural intervention that encourages inhabitants’ participation in the self-rehabilitation of their neighbourhood. The building phase is no longer considered as a parenthesis in inhabitants’ lives but as an important opportunity for public expression and civic participation.

BACKGROUND AND PURPOSE Choline analogues, a new type of antimalarials, exert potent in vitro and in vivo antimalarial activity. This has given rise to albitiazolium, which is currently in phase II clinical trials to cure severe malaria. Here we dissected its mechanism of action step by step from choline entry into the infected erythrocyte to its effect on phosphatidylcholine (PC) biosynthesis. EXPERIMENTAL APPROACH We biochemically unravelled the transport and enzymatic steps that mediate de novo synthesis of PC and elucidated how albitiazolium enters the intracellular parasites and affects the PC biosynthesis. KEY RESULTS Choline entry into Plasmodium falciparum-infected erythrocytes is achieved both by the remnant erythrocyte choline carrier and by parasite-induced new permeability pathways (NPP), while parasite entry involves a poly-specific cation transporter. Albitiazolium specifically prevented choline incorporation into its end-product PC, and its antimalarial activity was strongly antagonized by choline. Albitiazolium entered the infected erythrocyte mainly via a furosemide-sensitive NPP and was transported into the parasite by a poly-specific cation carrier. Albitiazolium competitively inhibited choline entry via the parasite-derived cation transporter and also, at a much higher concentration, affected each of the three enzymes conducting de novo synthesis of PC. CONCLUSIONS AND IMPLICATIONS Inhibition of choline entry into the parasite appears to be the primary mechanism by which albitiazolium exerts its potent antimalarial effect. However, the pharmacological response to albitiazolium involves molecular interactions with different steps of the de novo PC biosynthesis pathway, which would help to delay the development of resistance to this drug.

Cationic antimicrobial peptides (CAPs) play important roles in host immune defenses. Plectasin is a defensin-like CAP isolated from the saprophytic fungus Pseudoplectania nigrella . NZ2114 is a novel variant of plectasin with potent activity against Gram-positive bacteria. In this study, we investigated (i) the in vivo pharmacokinetic and pharmacodynamic (PK/PD) characteristics of NZ2114 and (ii) the in vivo efficacy of NZ2114 in comparison with those of two conventional antibiotics, vancomycin or daptomycin, in an experimental rabbit infective endocarditis (IE) model due to a methicillin-resistant Staphylococcus aureus (MRSA) strain (ATCC 33591). All NZ2114 regimens (5, 10, and 20 mg/kg of body weight, intravenously [i.v.], twice daily for 3 days) significantly decreased MRSA densities in cardiac vegetations, kidneys, and spleen versus those in untreated controls, except in one scenario (5 mg/kg, splenic MRSA counts). The efficacy of NZ2114 was clearly dose dependent in all target tissues. At 20 mg/kg, NZ2114 showed a significantly greater efficacy than vancomycin ( P < 0.001) and an efficacy similar to that of daptomycin. Of importance, only NZ2114 (in 10- and 20-mg/kg regimens) prevented posttherapy relapse in cardiac vegetations, kidneys, and spleen, while bacterial counts in these target tissues continued to increase in vancomycin- and daptomycin-treated animals. These in vivo efficacies were equivalent and significantly correlated with three PK indices investigated: f C max /MIC (the maximum concentration of the free, unbound fraction of a drug in serum divided by the MIC), f AUC/MIC (where AUC is the area under the concentration-time curve), and f % T >MIC (% T >MIC is the cumulative percentage of a 24-h period that the drug concentration exceeds the MIC under steady-state pharmacokinetic conditions), as analyzed by a sigmoid maximum-effect ( E max ) model ( R 2 > 0.69). The superior efficacy of NZ2114 in this MRSA IE model suggests the potential for further development of this compound for treating serious MRSA infections.

Ferroquine (FQ, SSR97193) is currently the most advanced organo-metallic drug candidate and about to complete phase II clinical trials as a treatment for uncomplicated malaria. This ferrocene-containing compound is active against both chloroquine-susceptible and chloroquine-resistant Plasmodium falciparum and P. vivax strains and/or isolates. This article focuses on the discovery of FQ, its antimalarial activity, the hypothesis of its mode of action, the current absence of resistance in vitro and recent clinical trials.

RESUME**: 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).

In most European countries, the way collective action is conducted has been transformed. The role of the State has been redesigned and the participation of a diversity of stakeholders, from the public and the private (for-profit and non-profit) sectors, has been encouraged. These changes are at the core of Welfare State reforms and concern many social fields such as care services and childcare ones in particular. From this perspective, this article analyses the changes in childcare services provision and regulation with a focus on the interactions between public, non-profit and for-profit players and on the collective stakes generated by these evolutions.; La plupart des pays européens manifeste une évolution des modes de gestion de l'action collective, modifiant le rôle de l'Etat et impliquant une diversité d'acteurs, publics et privés. Ces évolutions, au cœur de la réforme des Etats-Providence, concernent plusieurs champs de politiques sociales, notamment ceux du care, et en particulier les services d'accueil de la petite enfance. Cet article analyse les mutations du secteur de la petite enfance sous l'angle des interactions entre acteurs publics, associatifs et privés commerciaux et des enjeux collectifs qui en découlent.

The discovery of Streptomyces-produced streptomycin founded the age of tuberculosis therapy. Despite the subsequent development of a curative regimen for this disease, tuberculosis remains a worldwide problem, and the emergence of multidrug-resistant Mycobacterium tuberculosis has prioritized the need for new drugs. Here we show that new optimized derivatives from Streptomyces-derived griselimycin are highly active against M. tuberculosis, both in vitro and in vivo, by inhibiting the DNA polymerase sliding clamp DnaN. We discovered that resistance to griselimycins, occurring at very low frequency, is associated with amplification of a chromosomal segment containing dnaN, as well as the ori site. Our results demonstrate that griselimycins have high translational potential for tuberculosis treatment, validate DnaN as an antimicrobial target, and capture the process of antibiotic pressure-induced gene amplification.

Ferroquine (SSR97193) has been shown to be a promising antimalarial, both on laboratory clones and on field isolates. So far, no resistance was documented in Plasmodium falciparum. In the present work, the metabolic pathway of ferroquine, based on experiments using animal and human hepatic models, is proposed. Ferroquine is metabolized mainly via an oxidative pathway into the major metabolite mono-N-demethyl ferroquine and then into di-N,N-demethyl ferroquine. Some other minor metabolic pathways were also identified. Cytochrome P450 isoforms 2C9, 2C19, and 3A4 and, possibly in some patients, isoform 2D6, are mainly involved in ferroquine oxidation. The metabolites were synthesized and tested against the 3D7 (chloroquine-sensitive) and W2 (chloroquine-resistant) P. falciparum strains. According to the results, the activity of the two main metabolites decreased compared with that of ferroquine; however, the activity of the mono-N-demethyl derivative is significantly higher than that of chloroquine on both strains, and the di-N-demethyl derivative remains more active than chloroquine on the chloroquine-resistant strain. These results further support the potential use of ferroquine against human malaria.

Local governance in diversifying reception methods : a new challenge in social cohesion. As the objectives of family and employment policies converge, processes to structure and organise reception methods for infants involve many parties, each with different skills, rationales and interests. The increase in the number of parties involved, from the non-profit and private sectors to local authorities and including family centres and families, makes the concept of « governance » particularly effective. Based on monograph analyses conducted in Rennes and Montreuil, the authors demonstrate that although action rationales and diversification policies give « decentralised » parties more than their due, this does not, however, mean greater equality of consideration of the interest and positions of all parties involved in the sector. Policy remains poorly co-ordinated and frequently results from approaches based on mutual understandings and discussions. In sum, despite European drives to ensure that care action policy is firmly anchored in the region and truly open to all stakeholders, policy remains largely opaque and poorly concerted., À la confluence, dans leurs objectifs, des politiques familiales et d’emploi, la structuration et l’organisation des modes d’accueil de la petite enfance font intervenir de nombreux acteurs aux champs de compétences, logiques et intérêts différents. Du secteur lucratif ou non aux municipalités en passant par les CAF et les familles, la multiplication des intervenants rend tout à fait opérante la notion de « gouvernance ». À partir d’analyses monographiques réalisées à Rennes et à Montreuil, les auteurs montrent que les logiques d’action et les politiques de diversification, si elles font la part belle aux acteurs « décentralisés », ne signifient pas pour autant une plus grande égalité d’accès aux instances de direction ni une meilleure prise en compte des intérêts et des positions de tous les acteurs du secteur. Les politiques demeurent peu coordonnées, souvent marquées par des logiques d’ententes et de concertations bilatérales. Au final, malgré les volontés européennes de faire de ces politiques de garde des actions ancrées dans le territoire et vraiment ouvertes à l’ensemble des parties prenantes, elles demeurent largement opaques et peu concertées., Eme Bernard, Fraisse Laurent. La gouvernance locale de la diversification des modes d’accueil : un nouvel enjeu de « cohésion sociale ». In: Recherches et Prévisions, n°80, 2005. Acteurs et politiques de la petite enfance. Permanences et mutations. pp. 7-23.