15 research outputs found
1,2,3,4,8,9,10,11-Octahydrobenzo[<i>j</i>]phenanthridine-7,12-diones as New Leads against Mycobacterium tuberculosis
Tuberculosis
(TB) continues to be a worldwide health problem with
over 1.4 million deaths each year. Despite efforts to develop more
effective vaccines, more reliable diagnostics, and chemotherapeutics,
tuberculosis remains a threat to global health, fueled by the HIV
pandemic and the rapid generation of drug resistance. The exploration
of novel drugs to serve as a companion drug for existing drugs is
of paramount importance. As part of our program to design new 2-aza-anthraquinones
with antimycobacterial activity, various tetrahydro- and octaÂhydroÂbenzoÂ[<i>j</i>]ÂphenanthridineÂdiones were synthesized. These compounds
showed high in vitro potency against Mycobacterium
tuberculosis, the etiological agent of TB and against
other clinically relevant mycobacterial species at submicromolar concentrations.
The susceptibility of a multidrug resistant strain toward these compounds
and their ability to target intracellular replicating Mycobacterium tuberculosis was demonstrated. Next
to the acute toxicity, the genotoxicity of these compounds was investigated.
Often overlooked in studies, genotoxicity could be dismissed for the
investigated compounds, making them a promising scaffold in TB drug
research
Number of MDR with first-line drug resistance only, pre-XDR and XDR isolates in the study cohort.
<p>Number of MDR with first-line drug resistance only, pre-XDR and XDR isolates in the study cohort.</p
Evolution of the resistance profile of serial isolates obtained from 24 patients.
<p>For these 24 MDR-TB patients out of 37 with multiple isolates, resistance to additional drugs was observed during treatment. Legend: ▪ = Susceptible, ▪ = Resistant, −Test not performed, I: Isoniazid, R: Rifampicin, E: Ethambutol, Z: Pyrazinamid, Rb: Rifabutin, Ofl: Ofloxacin, Amk: Amikacin, Thio: Thioamide, Cap: Capreomycin NA = Not Applicable as less than 2 isolates were FLP profiled, so no conclusion possible.</p
Characteristics of the 58 MDR-TB patients in strain-clusters and results of epidemiological investigation.
<p>Legend: Y = yes; N = no, U = unknown; − = not applicable.</p
Repartition of the clusters according to the links identified between the patients.
<p>Clusters are represented by unique identification numbers. Next to the cluster number, the number of patients for who an epidemiological link was detected is indicated (i.e. 2/3: two of the three patients included in the cluster present this link). f: familial link; o: same geographic origin; p: geographic proximity. Clusters in orange contain more than 3 patients and cluster in grey more than 6. The purple boxes indicate the number of clusters belonging to each category (or combination of categories) of links. The blue boxes indicate clusters comprising exclusively Belgian-born patients. The green boxes indicate clusters with strains presenting the 776000000000171 spoligotype (S-family).</p
Characteristics of <i>Mycobacterium tuberculosis</i> complex strains isolated from tuberculosis patients living in Brussels and two subgroups; no-clustered and clustered strains, 2010–2013.
<p>Characteristics of <i>Mycobacterium tuberculosis</i> complex strains isolated from tuberculosis patients living in Brussels and two subgroups; no-clustered and clustered strains, 2010–2013.</p
Molecular epidemiology of <i>Mycobacterium tuberculosis</i> complex in Brussels, 2010–2013
<div><p>The tuberculosis (TB) incidence rate in Brussels-Capital Region is 3-fold higher than in Belgium as a whole. Eight years after the realization of initial prospective population-based molecular epidemiology investigations in this Region, a similar study over the period 2010–2013 was conducted. TB strains isolated from 945 patients were submitted to genotyping by standardized 24-locus-MIRU-VNTR typing and spoligotyping. The phylogenetic analysis showed that the LAM (16.7%) and Haarlem (15.7%) branches are the two most prevalent TB lineages circulating in Brussels. Analysis of the MDR subgroup showed an association with Beijing strains (39.9%) and patients native of Eastern Europe (40.7%). Genotyping detected 113 clusters involving 321 patients, giving a recent transmission index of 22.9%. Molecular-guided epidemiological investigations and routine surveillance activities revealed family transmission or social contact for patients distributed over 34 clusters. Most of the patients were foreign-born (75.7%). However, cluster analysis revealed only limited trans-national transmission. Comparison with the previous study shows a stable epidemiological situation except for the mean age difference between Belgian-born and foreign-born patients which has disappeared. This study confirms that molecular epidemiology has become an important determinant for TB control programs. However, sufficient financial means need to be available to perform all required epidemiological investigations.</p></div
Spleen cell IFN-γ production in response to <i>M</i>. <i>avium</i> culture filtrate (5 μg/mL) in BALB/c mice infected for 5 weeks (filled bars) or 20 weeks (striped bars) with the different <i>Mah</i> isolates.
<p>Results represent mean IFN-γ levels (pg/mL) ± SEM of 3–5 mice tested individually. Statistical significance is depicted for each human or porcine strain as compared to respectively Hu<b>91</b> or Po<b>91</b> (*: p<0.05). N.A.: not available.</p
Genes present at 100% identity in the sequenced <i>Mah</i> strains.
<p>Genes present at 100% identity in the sequenced <i>Mah</i> strains.</p
IFN-γ response of BALB/c mice infected intranasally with porcine MST12 isolate (Po12).
<p>Mice (n = 5) were sacrificed 5 weeks post-infection and pooled spleen cells were stimulated for 72h with each of the 35 <i>Map</i> antigens (5 μg/mL). IFN-γ levels are expressed in pg/mL.</p