Discovering new tuberculosis drugs

2000

Challenge

Current tuberculosis (TB) treatment regimens require people to take several antibiotic drugs for at least six months. The difficulty in adhering to these treatments has contributed to the emergence of drug-resistant strains of Mycobacterium tuberculosis (Mtb), the bacterium that causes the disease.

Advance

In the late 1990s, IRP researchers led by Clifton Barry, Ph.D., tested more than 60,000 compounds related to the TB drug ethambutol. They identified several compounds that were effective against Mtb in the laboratory and collaborated with industry on further drug development. Animal studies revealed that a compound called SQ109 kills Mtb, including drug-resistant strains. Then in 2000, IRP scientists and collaborators reported the discovery of another potential TB drug, PA-824, that may be effective against latent TB infections.

Impact

Early human clinical studies indicated that SQ109 is safe, and additional clinical trials are currently underway to evaluate SQ109’s effectiveness. The FDA has granted SQ109 Orphan Drug and Fast Track status, which could help accelerate eventual FDA approval. PA-824 entered clinical trials in 2005, and initial results suggest that it is safe and effective. Follow-on trials will aim to determine if it too could be headed towards the pathway of approval and use within the TB armamentarium.

Publications

Stover CK, Warrener P, VanDevanter DR, Sherman DR, Arain TM, Langhorne MH, Anderson SW, Towell JA, Yuan Y, McMurray DN, Kreiswirth BN, Barry CE, Baker WR. (2000). A small-molecule nitroimidazopyran drug candidate for the treatment of tuberculosis. Nature. 405(6789), 962-6.

Protopopova M, Hanrahan C, Nikonenko B, Samala R, Chen P, Gearhart J, Einck L, Nacy CA. (2005). Identification of a new antitubercular drug candidate, SQ109, from a combinatorial library of 1,2-ethylenediamines. J Antimicrob Chemother. 56(5), 968-74.

Singh R1, Manjunatha U, Boshoff HI, Ha YH, Niyomrattanakit P, Ledwidge R, Dowd CS, Lee IY, Kim P, Zhang L, Kang S, Keller TH, Jiricek J, Barry CE 3rd. (2008). PA-824 kills nonreplicating Mycobacterium tuberculosis by intracellular NO release. Science. 322(5906), 1392-5.

Wallis RS, Jakubiec W, Mitton-Fry M, Ladutko L, Campbell S, Paige D, Silvia A, Miller PF. (2012). Rapid evaluation in whole blood culture of regimens for XDR-TB containing PNU-100480 (sutezolid), TMC207, PA-824, SQ109, and pyrazinamide. PLoS One. 7(1), e30479.

KA Sacksteder, M Protopopova, CE Barry 3rd, K Andries, CA Nacy. (2012). Discovery and development of SQ109: a new antitubercular drug with a novel mechanism of action. Future Microbiol. 7(7), 823-37.

Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, Via LE, Goldfeder LC, Kang E, Jin B, Park H, Kwak H, Kim H, Jeon HS, Jeong I, Joh JS, Chen RY, Olivier KN, Shaw PA, Follmann D, Song SD, Lee JK, Lee D, Kim CT, Dartois V, Park SK, Cho SN, Barry CE 3rd. (2012). Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med. 367(16), 1508-18.