Making antisense of TB

Tuberculosis (TB) is a devastating infectious disease that causes ∼3 million deaths annually. The causative agent, Mycobacterium tuberculosis, infects approximately one-third of the world’s population. The prevalence of multidrug-resistant M. tuberculosis underscores the urgent need for novel strategies to combat this pathogen. New anti-TB treatments must either be aimed at new molecular targets or have a different mode of action.The formidable barrier formed by the cell wall of M. tuberculosis thwarts the action of most anti-TB drugs. The overall structure of the cell wall consists of a waxy, almost impenetrable mycolic acid coating. Pathogenic M. tuberculosis releases a high concentration of glutamine synthetase (GS) into the extracellular milieu and contain large amounts of poly-l-glutamate/glutamine (P–L–Glx) in their cell wall. The high correlation between GS export and the presence of P–L–Glx in the cell wall suggests an important role for GS in cell wall synthesis.Now, Harth et al.1xTreatment of Mycobacterium tuberculosis with antisense oligonucleotides to glutamine synthetase mRNA inhibits glutamine synthetase activity, formation of the poly-l-glutamate/glutamine cell wall structure, and bacterial replication. Harth, G. et al. Proc. Natl. Acad. Sci. U. S. A. 2000; 97: 418–423Crossref | PubMed | Scopus (100)See all References1 have reported on the ability of phosphorothioate-modified antisense oligonucleotides (PS-ODNs) to inhibit GS activity, formation of P–L–Glx polymers in the cell wall and bacterial replication by base pairing with the GS mRNA transcript. The results indicate that PS-ODNs can traverse the cell wall and bind their cognate targets in the cytoplasm. The reduction in the P–L–Glx heteropolymer is a consequence of diminished GS levels and is postulated to affect cell growth by disturbing cell wall integrity. The antisense therapy did not affect the growth of Mycobacterium smegmatis, a non-pathogenic strain that does not export GS or have P–L–Glx in its cell wall. This study demonstrates a highly specific therapy that could be a feasible weapon in the arsenal against TB.