Editor's ChoiceTuberculosis

New Antibacterial Drug Destroys Dormant Bugs

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Science Translational Medicine  07 Oct 2009:
Vol. 1, Issue 1, pp. 1ec2
DOI: 10.1126/scitranslmed.3000440

Hidden in lung macrophages of one-third of the human population is a bacterium—Mycobacterium tuberculosis—that causes a disease once thought to have been eradicated by screening, vaccination, and antibiotics. According to the World Health Organization’s 2009 report, tuberculosis killed 1.5 million people worldwide in 2006. The M. tuberculosis organism can live in a host for many years in a dormant, nonreplicating state that is resistant to traditional antibiotics that kill bacteria by inhibiting RNA or protein synthesis. Such conditions can give rise to dangerous multidrug-resistant bacteria, which are easily spread by a cough or a sneeze—any action that creates an aerosol. New antibacterial drugs are needed that destroy the dormant organism and cure carriers of this destructive disease. Now, Lin et al. have discovered a molecule that kills M. tuberculosis by inhibiting the proteasome, a molecular machine found in all eukaryotes and in mycobacteria, that degrades damaged or superfluous proteins. Because proteasomes are highly conserved throughout evolution, inhibitors of these structures have proven to be too toxic for use as anti-infective drugs. However, in the new work, investigators have identified and characterized compounds that selectively inhibit the M. tuberculosis, but not the human, proteasome by modifying a threonine amino acid in the bacterial proteasome’s active site. These compounds do not kill monkey epithelial cells, human macrophages, or a variety of bacteria other than M. tuberculosis. It might be beneficial to treat patients simultaneously with two antibiotics, one that blocks transcription or translation in active bacteria and one that disrupts the proteasome and kills dormant bugs. This approach may permit patients to take the antibiotics for shorter periods of time and thus reduce the emergence of resistant bacterial strains.

G. Lin et al., Inhibitors selective for mycobacterial versus human proteasomes. Nature 461, 621–626 (2009). http://www.nature.com/nature/journal/v461/n7264/full/nature08357.html

Citation: K. LaMarco, New Antibacterial Drug Destroys Dormant Bugs, Sci. Transl. Med. 1, 1ec2 (2009).

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