Dual-Pharmacophore Pyrithione-Containing Cephalosporins Kill Both Replicating and Nonreplicating Mycobacterium tuberculosis

The historical view of β-lactams as ineffective antimycobacterials has given way to growing interest in the activity of this class against Mycobacterium tuberculosis (Mtb) in the presence of a β-lactamase inhibitor. However, most antimycobacterial β-lactams kill Mtb only or best when the bacilli are replicating. Here, a screen of 1904 β-lactams led to the identification of cephalosporins substituted with a pyrithione moiety at C3′ that are active against Mtb under both replicating and nonreplicating conditions, neither activity requiring a β-lactamase inhibitor. Studies showed that activity against nonreplicating Mtb required the in situ release of the pyrithione, independent of the known class A β-lactamase, BlaC. In contrast, replicating Mtb could be killed both by released pyrithione and by the parent β-lactam. Thus, the antimycobacterial activity of pyrithione-containing cephalosporins arises from two mechanisms that kill mycobacteria in different metabolic states

Trypanosoma cruzi infection patterns in intact and athymic mice of susceptible and resistant genotypes

Inbred strains of mice inoculated with the T. cruzi Y strain behaved as susceptible (A/J, C3H/HeN), intermediate (BALB/c) or relatively resistant (C57BL/6) with respect to the magnitude of parasitaemia and mortality rate. C57BL/10 mice were susceptible in relation to parasitaemia but resistant when mortality was analyzed. Infection with T. cruzi CL strain presented the same results, except for C57BL/6 which behaved as susceptible mice. Athymic mice of various backgrounds revealed no differences in susceptibility, presenting the same dramatic parasitaemia, tissue colonization pattern and no inflammatory reaction in any of the tissues studied. Infection of euthymic and athymic BALB/c mice elicited the production of parasite-specific antibodies, which reached similar levels on the first 9 days but differed after day 13. Serum transfer experiments in BALB/c mice did not show great differences in parasitaemia but altered T. cruzi polymorphism reducing the slender forms in athymic mice. Histopathology of athymic BALB/c mice showed the same tissue tropism when infected either with T. cruzi Y or CL strain

Rôle des cellules dendritiques humaines dans la tuberculose : protecteur ou non protecteur ?

International audienceMycobacterium tuberculosis, the cause of tuberculosis remains a pathogenic organism capable of infecting a large number of individuals and of resisting the immune response of the infected host. The main constituents of this response are the antigen presenting cells such as dendritic cells, macrophages and T lymphocytes.IntroductionMycobacterium tuberculosis, agent de la tuberculose, reste un organisme pathogène capable d’infecter un grand nombre d’individus, et de résister à la réponse immune de l’hôte infecté. Les acteurs principaux de cette réponse immune sont les cellules présentatrices d’antigènes comme les cellules dendritiques, les macrophages et les lymphocytes T.État des connaissancesL’étude comparative des interactions entre M. tuberculosis et les cellules présentatrices d’antigène a permis de montrer que les cellules dendritiques ne permettent pas la croissance intracellulaire de M. tuberculosis, à la différence de ce que l’on observe dans les macrophages. Un compartiment intracellulaire hostile crée les conditions d’une bactériostase. M. tuberculosis st internalisé en se liant à un récepteur des cellules dendritiques de type lectine (DC-SIGN).PerspectivesCe récepteur reconnaît des composés sucrés que l’on retrouve à la surface de la paroi de M. tuberculosis. Ce lien sucres-lectine pourrait compenser le lien composés bactériens-récepteur de type Toll, inhibant partiellement la réaction inflammatoire protectrice, ou compensant une réaction inflammatoire excessive.ConclusionsCe lien favoriserait également la persistance de la bactérie à l’état quiescent dans les cellules dendritiques, et l’adaptation réciproque de l’hôte et de la bactérie au cours du temps