Tuberculosis is an infectious disease caused by M.tuberculosis (MTB) that attacks the lung and is spread from person to person through the air. MDR-TB (multi-drug resistant tuberculosis) has become a global threat and is a very dangerous form of tuberculosis. It occurs when TB is not properly treated. Then these TB germs become resistant to first line TB drugs. The predominant drugs used for TB treatment are isoniazid, rifampicin, pyrazinamide and ethambutol, which target the cell wall of the bacteria. These drugs work well with patients who are infected by normal MTB bacteria. However, patients with MDR-TB require a combination of drugs, which often cause undesirable side effects. Also, a combination of the currently available drugs is not guaranteed to be efficacious. Thus, the development of new anti-TB drugs that are effective against MDR-TB strains is an urgent need.

FtsZ, is an essential protein for bacterial cell division and compounds that interfere with FtsZ function have an excellent potential as antituberculosis agents. FtsZ is a homolog to tubulin. Since taxanes have been known to interfere with tubulin polymerization, they might also be able to interfere with FtsZ polymerization. Therefore, taxanes are promising lead compounds for developing anit-TB agents.

Preliminary studies have shown that several taxanes have good anti-TB activity, especially against MDR-TB. The lead taxane is SB-RA-2001. My project involves optimization of taxane lead SB-RA-2001 for anti-TB activity. First, I need to optimize the position of the 3-naphthylacrylic acid side chain. I attached this side chain moiety to the C-7, C-10, and both positions to see its effects on their anti-TB activity. Secondly, due to the poor water solubility of
SB-RA-2001, I added an amino acid side chain to the C-7 position of the modified SB-RA-2001. This side chain will have the ability for salt formation, making the compound more water-soluble. All synthesized taxanes will be evaluated their anti-TB activity at Dr. Kirikae's laboratory in the International Medical Center of Japan.

This research was supported by a fellowship (to R.R.) from the Simons Foundation and grants from the National Institute of Health and the Japan Health Science Foundation (to I.O.)