Current News
17 September 2009Nature, edited by Infection Research
Tuberculosis: Promising drug candidates identified
US-Scientists have identified a new class of molecules that inhibit the proteasome of Mycobacterium tuberculosis while largely sparing the human homologue. Due to this selectivity, the compounds are promising candidates for the development of new drugs to treat tuberculosis, Carl Nathan (Weill Cornell Medical College, New York) and colleagues report in the journal Nature.
Mycobacteria are the only bacterial pathogens known to have proteasomes, extensively conserved protein complexes that degrade damaged or unneeded proteins. As research has shown that M. tuberculosis needs the proteasome to persist in mice, the complex is regarded as a possible drug target. Scientists have been searching for compounds to inhibit the proteasome, but so far all the molecules tested have inhibited mammalian proteasomes more potently than those of M. tuberculosis.
Among 20,000 compounds screened, Carl Nathan and colleagues have now found two molecules that selectively and irreversibly inhibit the M. tuberculosis proteasome. These molecules - oxathiazol-2-one compounds named GL5 and HT1171 - "act as selective suicide-substrate inhibitors of the M. tuberculosis proteasome by cyclocarbonylating its active site threonin“, the scientists write in Nature. Tests showed, that while the compounds kill mycobacteria, they show no apparent toxicity to mammalian cells.
Especially advantageous is the fact, that the compounds kill non-replicating bacteria, which are hard to combat with existing drugs; the relative resistance of mycobacteria to conventional anti-infectives translates into very long treatment periods - months or even years - for actively infected persons. "Prolonged treatment leads to interruption of therapy and emergence of hereditable drug resistance. Hence agents are needed that can kill M. tuberculosis when its replication is halted by conditions in the host (...)“, the scientists write.
Also see:
- General information on tuberculosis
- Meet Carl Nathan on Infection Research
Gang Lin, Dongyang Li, Carl Nathan et al. Inhibitors selective for mycobacterial versus human proteasomes. Nature advance online publication 16 September 2009, doi:10.1038/nature08357
