A systematic review of utility of urine lipoarabinomannan in detecting tuberculosis among HIV-positive tuberculosis suspects.

Sputum smear microscopy (SSM), though regarded as an inexpensive and popular method for detecting tuberculosis (TB), lacks adequate sensitivity, specifically in adult people living with HIV/AIDS (PLHIV). Urine lipoarabinomannan (LAM) is a promising diagnostic tool among PLHIV with CD4 cell count < 200 cells/µl. We attempted to review all the studies undertaken in identifying the utility of urine LAM in diagnosing TB, especially among PLHIV. We searched PubMed, Google Scholar, and MEDLINE databases for studies reporting diagnostic utility of urine LAM status in PLHIV, published in the last 20 years till December 2019. The keywords used for searching were "Tuberculosis," "HIV/AIDS," "Diagnosis," "Screening" "Lipoarabinomannan," and "Urine." Our search resulted in 137 shortlisted citations, of which 67 related manuscripts were identified for detailed study. Based on inclusion and exclusion criteria, 37 studies were reviewed in detail. Average sample size of these studies was 464 (range = 81-2528; SD = 427). Crude average sensitivity of urine LAM in culture-confirmed TB cases was 44.1% (range = 8.3-93) while that of SSM was 38.6% (range = 14-65). However, sensitivity of urine LAM + SSM was 60.4% (range = 38.3-92.7), demonstrating the utility of SSM + urine LAM combination for detecting TB. Specificity was similar between urine LAM and SSM with 92.7% (range = 76-100) and 97.9% (range = 93.9-100), respectively. Majority of the studies demonstrated higher sensitivity of urine LAM in those with lesser the CD4 count, with immunocompromised and with debilitation who cannot produce self-expectorated sputum. We conclude that urine LAM is a potential diagnostic test in the algorithms involving immunocompromised, debilitated patients and specifically in PLHIV whose CD4 count is ≤100 cells/µl.

Synthesis, Antimycobacterial Evaluation and Docking Studies of Some 7-Methyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-ones.

Two series of 3-substituted-7-methyl-5,6,7,8-tetrahydropyrido[4',3':4,5] thieno[2,3-d]pyrimidin-4(3H)-one (6a-k) and 3-substituted-7,2-dimethyl-5,6,7,8-tetrahydropyrido[4',3':4,5]thieno[2,3-d]pyrimidin-4(3H)-one (7a-k) derivatives were synthesized and characterized using spectral data i.e., IR, 1H-, 13C-NMR, Mass and CHN elemental analyses. The synthesized compounds were evaluated for antibacterial activity against each of two strains of Gram-positive (Bacillus subtilis and Staphylococcus aureus) and Gram-negative (Escherichia coli and Klebsiella pneumoniae) bacteria and antimycobacterial activity screened against two strains i.e., Mycobacterium tuberculosis (MTB) H37Rv and an isoniazid-resistant clinical sample. Further to validate potentiality of our design was analyzed using molecular docking studies by taking crystal structure of MTB pantothenate synthetase (MTB-PS) (PDB: 3IVX). In this study, some compounds 6k (Minimum Inhibitory Concentration (MIC): MIC-22 µM), 7d (MTB: MIC-22 µM) and 7k (MTB: MIC-11 µM) showed potential antibacterial and antimycobacterial activities.

Novel drug targets for Mycobacterium tuberculosis: 2-heterostyrylbenzimidazoles as inhibitors of cell wall protein synthesis.

BACKGROUND: Multi drug-resistant and mycobacterial infections are a major public health challenge, leading to high mortality and socioeconomic burdens through worldwide. Novel therapeutics are necessary to treat the drug resistant strains, since no new chemical entities are emerged in the last four decades for the treatment of TB. FINDINGS: A series of novel 2-heterostyrylbenzimidazole derivatives were synthesised by cyclisation of (3,4-diaminophenyl)(phenyl)methanone, cinnamic acid using glycerol in high yield. The molecular structures of target compounds (5a-5n) were confirmed by 1H and 13C NMR spectroscopy and mass spectrometry. Newly synthesized compounds were screened for anti-tubercular activity and the MIC was determined against Mycobacterium tuberculosis H37Rv by broth microdilution method using Lowenstein Jensen medium (LJ). These compounds docked into the active site of "Crystal structure of pantothenate synthetase in complex with 2-(2-(benzofuran-2-ylsulfonylcarbamoyl)-5-methoxy-1H-indol-1-yl)acetic acid" (PDB code, 3IVX). Auto dock 4.2 software was used for docking studies. RESULTS: 5d, 5e, 5f, 5g, 5i, and 5l show better activity and the most active inhibitor of tuberculosis 5f showed a promising inhibition of M. tuberculosis with MIC value of 16 µg/mL. The molecules functionalized with electron-donating groups (Cl, O, S, etc.) on different aromatic aldehydes (5a-5n) were found to be more active in inhibiting M. tuberculosis. CONCLUSIONS: On the basis of docking studies, 5f has shown good affinity for the enzyme. Comparison was made with the binding energies of the standard drugs amoxicillin (-34.28 kcal/mol) and ciprofloxacin (-28.20 kcal/mol). Among all the designed compounds, the compound 5f shows highest binding energy with two amino acid interactions Lys160, Val187 (-9.80 kcal/mol).