A prospective longitudinal study evaluating a T-cell-based assay for latent tuberculosis infection in health-care workers in a general hospital in Beijing / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The health-care workers (HCWs) are at high risk of acquiring infection with Mycobacterium tuberculosis. The objectives of this study were to compare the performance of the T-SPOT.TB and tuberculin skin test (TST) for latent tuberculosis infection (LTBI), evaluate diagnostic concordance and risk factors for LTBI, and observe the progression to active tuberculosis (TB) disease among HCWs in a general hospital in Beijing.</p><p><b>METHODS</b>The prospective cohort study enrolled HCWs in a tertiary general hospital in Beijing, China, to evaluate LTBI with T-SPOT.TB and TST. The subjects were evaluated every 12 months during the 60-month follow-up.</p><p><b>RESULTS</b>Of 101 participating HCWs, 96 and 101 had valid TST and T-SPOT.TB results, respectively. Twenty-nine (28.7%, 95% confidence interval (CI), 19.9% - 37.5%) were defined as positive by T-SPOT.TB and 53 (55.2%, 95%CI, 45.2% - 64.9%) were defined as positive by TST (using a ≥ 10 mm cutoff). An agreement between the two tests was poor (57.3%, κ = 0.18, 95%CI, 0.01% - 0.52%). In multivariate analysis, direct exposure to sputum smear-positive TB patients was a significant risk factor for a positive T-SPOT.TB (OR 5.76; 95%CI 1.38 - 24.00). Pooled frequency of antigen-specific IFN-γ secreting T-cells for subjects who reported direct contact with sputum smear-positive TB patients was significantly higher than that for participants without direct contact (P = 0.045). One of 20 participants with positive result of T-SPOT.TB and TST developed active TB at 24-month follow-up.</p><p><b>CONCLUSION</b>T-SPOT.TB is a more accurate, targeted method of diagnosing LTBI than TST.</p>

Identification of arylamine N-acetyltransferase inhibitors as an approach towards novel anti-tuberculars

New anti-tubercular drugs and drug targets are urgently needed to reduce the time for treatment and also to identify agents that will be effective against Mycobacterium tuberculosis persisting intracellularly. Mycobacteria have a unique cell wall. Deletion of the gene for arylamine N-acetyltransferase (NAT) decreases mycobacterial cell wall lipids, particularly the distinctive mycolates, and also increases antibiotic susceptibility and killing within macrophage of Mycobacterium bovis BCG. The nat gene and its associated gene cluster are almost identical in sequence in M. bovis BCG and M. tuberculosis. The gene cluster is essential for intracellular survival of mycobacteria. We have therefore used pure NAT protein for high-throughput screening to identify several classes of small molecules that inhibit NAT activity. Here, we characterize one class of such molecules-triazoles-in relation to its effects on the target enzyme and on both M. bovis BCG and M. tuberculosis. The most potent triazole mimics the effects of deletion of the nat gene on growth, lipid disruption and intracellular survival. We also present the structure-activity relationship between NAT inhibition and effects on mycobacterial growth, and use ligand-protein analysis to give further insight into the structure-activity relationships. We conclude that screening a chemical library with NAT protein yields compounds that have high potential as anti-tubercular agents and that the inhibitors will allow further exploration of the biochemical pathway in which NAT is involved.