Intranasally administered S-MGB-364 displays antitubercular activity and modulates the host immune response to Mycobacterium tuberculosis infection.

Background: Previously, we evaluated the intracellular mycobactericidal activity of the minor groove binder, S-MGB-364 against the clinical Mycobacterium tuberculosis (Mtb) strain HN878 in macrophages.

Objectives: To assess the mycobactericidal activity of S-MGB-364 in Mtb-infected mice. Further, we investigated a plausible DNA binding mechanism of action of S-MGB-364.

Praziquantel Treatment of Infected Mice Renders Them Less Susceptible to Reinfection.

Beyond transient control of the infection, additional benefits of mass drug administration of praziquantel in endemic communities have been suggested in communities but not mechanistically investigated experimentally. The present study sought to evaluate the additional and hitherto unreported benefits of repeated mass drug administration of praziquantel. We used a tractable mouse model of infection to assess the effects of repeated infection-treatment cycles on the host susceptibility to reinfection.

IL-4i1 Regulation of Immune Protection During Mycobacterium tuberculosis Infection.

Background: Interleukin 4 (IL-4i1)-induced gene 1 encodes L-phenylalanine oxidase that catabolizes phenylalanine into phenylpyruvate. IL-4i1 is mainly expressed by antigen-presenting cells (APCs), inhibits T-cell proliferation, regulates B-cell activation, modulates T cell responses, and drives macrophage polarization, but its role in bacterial infections is understudied.

Methods: We evaluated IL-4i1 deletion in macrophages and mice on infection with virulent H37Rv and W-Beijing lineage hypervirulent HN878 Mycobacterium tuberculosis (Mtb) strains.

Investigating the antifibrotic effect of the antiparasitic drug Praziquantel in in vitro and in vivo preclinical models.

Tissue fibrosis underlies the majority of human mortality to date with close to half of all reported deaths having a fibrotic etiology. The progression of fibrosis is very complex and reputed irreversible once established. Although some preventive options are being reported, therapeutic options are still scarce and in very high demand, given the rise of diseases linked to fibroproliferative disorders.

Batf2 differentially regulates tissue immunopathology in Type 1 and Type 2 diseases.

Basic leucine zipper transcription factor 2 (Batf2) activation is detrimental in Type 1-controlled infectious diseases, demonstrated during infection with Mycobacterium tuberculosis (Mtb) and Listeria monocytogenes Lm. In Batf2-deficient mice (Batf2), infected with Mtb or Lm, mice survived and displayed reduced tissue pathology compared to infected control mice. Indeed, pulmonary inflammatory macrophage recruitment, pro-inflammatory cytokines and immune effectors were also decreased during tuberculosis.

Evaluation of minor groove binders (MGBs) as novel anti-mycobacterial agents and the effect of using non-ionic surfactant vesicles as a delivery system to improve their efficacy.

Objectives: The slow development of major advances in drug discovery for the treatment of Mycobacterium tuberculosis (Mtb) infection suggests a compelling need for evaluation of more effective drug therapies against TB. New classes of drugs are constantly being evaluated for anti-mycobacterial activity with currently a very limited number of new drugs approved for TB treatment. Minor groove binders (MGBs) have previously revealed promising antimicrobial activity against various infectious agents; however, they have not yet been screened against Mtb.

Host pregnancy influences the establishment of in Balb C mice.

In order to determine the effect of host pregnancy in the establishment of , 120 female Balb C mice were divided into 4 groups of 30 mice each. Group 1 animals were orally infected with 50 larvae per gram (LPG) of body weight on day 0; group 2 were mated on day 0 and not infected; group 3 were mated at day 0 and infected with 50 LPG at day 7 post-mating and Group 4 were control animals which were neither mated nor infected. Six animals from each group were sacrificed and the number of adult parasites in the intestines as well as larvae in the muscles were determined at day 0, 7, 14, 21 and 28 post-infection for group 1; 0, 7, 14, 21 and 28 post-mating for group 2 and days 7, 14, 21, 28 and 35 post-mating for group 3.

Host regulation of liver fibroproliferative pathology during experimental schistosomiasis via interleukin-4 receptor alpha.

Interleukin-4 receptor (IL-4Rα) is critical for the initiation of type-2 immune responses and implicated in the pathogenesis of experimental schistosomiasis. IL-4Rα mediated type-2 responses are critical for the control of pathology during acute schistosomiasis. However, type-2 responses tightly associate with fibrogranulomatous inflammation that drives host pathology during chronic schistosomiasis.

Interleukin-4 receptor alpha is still required after Th2 polarization for the maintenance and the recall of protective immunity to Nematode infection.

There is currently no vaccine against parasitic nematodes and the knowledge on the mechanisms by which protective immunity against this class of parasites is achieved is continuously expanding. Nematode parasites trigger a host protective type 2 immune response via interleukin-4 receptor alpha (IL-4Rα). Despite this central role, it is not known whether IL-4Rα has a role in maintaining host type 2 immune responses following polarization.

An evaluation of Minor Groove Binders as anti-fungal and anti-mycobacterial therapeutics.

This study details the synthesis and biological evaluation of a collection of 19 structurally related Minor Groove Binders (MGBs), derived from the natural product distamycin, which were designed to probe antifungal and antimycobacterial activity. From this initial set, we report several MGBs that are worth more detailed investigation and optimisation. MGB-4, MGB-317 and MGB-325 have promising MICs of 2, 4 and 0.