DRUGS

There are a number of drugs used to treat infectious diseases, with varying levels of success. Antibiotics are used to treat bacterial infections but these types of drugs have no effect on illnesses caused by viruses. The overuse of antibiotics has resulted in several types of bacteria – including the bacteria that causes tuberculosis – to develop resistance to one or more varieties of antibiotics. This makes the bacteria much more difficult to treat and creates a need to develop new, better drugs.

Drugs have been developed to treat some viral diseases, including AIDS, herpes, Hepatitis B and C and influenza. There are also antifungals as well as anti-parasitics, for diseases such as malaria. As new diseases emerge and resistance rises, the development of new drugs is essential.

TUBERCULOSIS DRUG DISCOVERY

CHALLENGE

Tuberculosis (TB) is a deadly disease that kills nearly 2 million people every year. Another 2 billion people, mostly living in the poorest areas, are estimated to be infected with the TB bacterium, Mycobacterium tuberculosis. The main drugs commonly used currently to treat TB were developed over 40 years ago and normally take 6 months to cure someone of disease. The lengthy treatment of TB makes curing those in the poorest communities a daunting challenge. To compound the problem, we are faced with an increasing threat from bacteria that are resistant to many of the drugs used to treat disease; in such cases antibiotic treatment can take 12-24 months.

SOLUTION

IDRI’s Tuberculosis Drug Discovery Group is focused on discovering and developing novel drugs that are effective at curing drug sensitive and drug resistant TB with the added goal of shortening the time it takes to cure disease. To maximize our chances for success, we have formed a multi-disciplinary team that combines the efforts of microbiologists, biochemists and chemists to:

  • Study the biology of TB bacteria in great detail to identify new metabolic pathways that may be vulnerable to drugs
  • Develop and apply innovative methods to discover new drug targets in the TB bacteria
  • Test thousands of potential drugs in our screening facility to find new compounds or new compound classes that kill TB bacteria
  • Develop biochemical screens to test compounds for their ability to prevent TB protein’s functioning normally
  • Develop novel screens using conditions that mimic those the TB bacteria encounters in the human body
  • Utilize medical chemistry to optimize the structures of compounds so that they kill TB bacteria in a more potent fashion and are non-toxic

IDRI is a founding member of the Lilly TB Drug Discovery Initiative and the TB Drug Accelerator (TBDA). The Lilly initiative is a unique public-private partnership with Eli Lilly and Company and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), with a focus on the discovery of new anti-tuberculosis drugs. The TBDA is a partnership of eight pharmaceutical companies and four other institutions funded in part by the Bill & Melinda Gates Foundation that targets the discovery of new TB drugs by collaborating on early-stage drug discovery for tuberculosis.

Identification of phenoxyalkylbenzimidazoles with anti-tubercular activity. 2015. N.S. Chandrasekera, T. Alling, M.A. Bailey, M. Files, J.V. Early, J. Ollinger, Y. Ovechkina, T. Masquelin, P.V. Desai, J.W. Cramer, P.A. Hipskind, J.O. Odingo, and T. Parish. J. Med Chem. 58: 7273-7285.

Putting tuberculosis (TB) to rest: transformation of the sleep aid, Ambien and “Anagrams” generated potent anti-tubercular agents. 2015. G.C. Moraski, P.A. Miller,. M.A. Bailey, J. Ollinger, T. Parish, H.I. Boshoff, S. Cho, J.R. Anderson, S. Mulugeta, S.G. Franzblau and M.J. Miller. ACS Infectious Diseases. 1: 85-90.

Optimization and evaluation of 5-styryl-2-oxathiazol-2-one Mycobacterium tuberculosis proteasome inhibitors as potential anti-tubercular agents. 2015. F. Russo, J. Gising, L. Akerbladh, A. Roos, A. Naworyta, S. Mowbray, A. Sokolowski, I. Hendersson, T. Alling, N. Bailey, M. Files, T. Parish, A. Karlen and M. Larhed. Chemistry Open. 4: 342 –362.

EmbC lead to alterations in Mycobacterium tuberculosis lipoarabinomannan. 2014. A. Korkegian, D.M. Roberts, R. Blair, T. Parish. Mutations in the essential arabinosyltransferase J Biol Chem. 289: 35172-35181.

Synthesis and evaluation of the 2,4-diaminoquinazolines series as anti-tubercular agents. 2014. J Odingo, T. O’Malley, E. Kesicki, M. Bailey, J. Early, S. Dalai, S. Sing, P.A. Hipskind, R Vickers and T. Parish. Bioorg Med Chem. 22:6965-6979.

A high-throughput screen against pantothenate synthetase (PanC) identifies 3-biphenyl-4-cyanopyrrole-2-carboxylic acids as a new class of inhibitor with activity against Mycobacterium tuberculosis. 2013. A. Kumar, A. Casey, J. Odingo, E.A. Kesicki, G. Abrahams, M. Vieth, T. Masquelin, V. Mizrahi, P.A. Hipskind, D.R. Sherman and T. Parish. PLOS One. 8: e72786.

Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. 2013. T.R. Ioerger, T. O’Malley, R. Liao, K.M. Guinn, M.J. Hickey, N. Mohaideen, K.C. Murphy, H.I.M. Boshoff, V. Mizrahi, E.J. Rubin, C.M. Sassetti, C.E. Barry III, D.R. Sherman, T. Parish, J.C. Sacchettini. PLOS One. 8: e75245.