Screening for TB combatants

One reason for the sharp increase in TB infections is the development of antibiotic-resistant TB strains, including some that are resistant to multiple drugs. It appears that it is only a matter of time before the current last resort drugs become useless against certain strains. Now, a combined effort between MediChem Life Sciences and the National Taiwan University has identified a potential new weapon against TB.

Biflavonoids are a group of highly conjugated, heterocyclic natural compounds containing flavone–flavone, flavanone–flavanone, and flavanone–flavone linkages. Since they were first isolated from plants in 1929, studies have found that they have a range of therapeutic effects.

The right stuff. This biflavone molecule showed the highest TB inhibition, 96%, of the 29 biflavonoids analyzed. Its key features include a 6–6´´ flavone linkage and a wealth of methoxy groups.

For this particular study, biflavonoids isolated from seed kernels of Rhus succedanea and Garcinia multiflora, and other ones generated from synthetic alterations, were tested for inhibition against a strain of Mycobacterium tuberculosis (Bioorg. Med. Chem. Lett. 2001, 11, 2101–2104). Groups of compounds with identical flavone or flavanone units but variations in linkage locations give dramatic differences in inhibition activity. For example, one flavone– flavone hexamethylether linkage at the 6–2´´´ location showed only 1% inhibition of TB (at 12.5 µg/mL), whereas the 6–6´´ linkage showed 96% inhibition.

In addition, certain functional groups are able to make or break the effectiveness of a molecule. Biflavanone linkages with hydroxy, acetoxy, or glucosyl groups had no effect on TB. However, the inclusion of a methoxy substituent on one of the compounds in this group resulted in an 87% inhibition. Similar results were found using a nitro group.

Therefore, the location of the linkage appears to be one of the most essential elements to TB inhibition. In addition, the presence of a methoxy or nitro group can be an important factor in establishing inhibitory behavior.

Now that these elements have been identified, mechanistic and pharmacological studies must be carried out to design a new class of drugs to treat TB and, hopefully, prove the WHO’s projections wrong.