Drug Discovery for Tuberculosis
Identifying and optimizing candidate compounds using a high-throughput multiassay platform
Tuberculosis (TB) causes ~1.5 million deaths per year and is the leading cause of death from infectious disease. TB is treated with a months-long regimen of multiple drugs. New medications that simplify and shorten TB treatment are urgently needed.
Working with Mycobacterium tuberculosis, the bacterium that causes TB, is difficult because it is slow-growing, can enter a non-replicating state, and exists both extracellularly and intracellularly within macrophages. These features of M. tuberculosis, along with the need for biosafety facilities to culture it, make discovering new TB drugs extremely challenging.
Dr. Parish has decades of experience working with mycobacteria. Her laboratory has the ability to work in a biosafety laboratory that is dedicated to cultivating these pathogenic bacteria. Her group has expertise in high-throughput screening of small molecule libraries using their adaptable multiassay platform that is validated for discovering and optimizing new drugs for TB. The Parish group runs the core platform assays continuously and can get results for some assays in as little as 2 weeks. The assays in the TB drug discovery platform range from multi-well growth assays and cytotoxicity tests, to measuring the ability of compounds to inhibit infection of human macrophages.
The Parish group capabilities include medicinal and synthetic chemistry for compound modification and lead optimization. The team can also develop probes and affinity labels for binding and affinity assays. They can identify drug targets and mechanisms using overexpression libraries or through isolation and sequencing of resistant mutants.
Seattle Children’s Research Institute is a member of the TB Drug Accelerator (TBDA), an international partnership of pharmaceutical companies, universities, government and foundation funders, and research institutes. The TBDA mission is to speed the discovery and development of novel TB drugs. Dr. Parish has extensive experience working within this consortium, including with industry collaborators.
Dr. Parish is interested in partnerships that lead to discovery and validation of new TB targets and drugs and optimization of candidate compounds. Her group can also test and optimize compounds under contract, using their customizable multiassay platform.
Stage of Development
- Preclinical in vitro
- Sponsored research agreement
- Collaborative research opportunity
- Consultation agreement
- High-throughput screening
- Small business collaboration
- Parish T. In vitro drug discovery models for Mycobacterium tuberculosis relevant for host infection. Expert Opin Drug Dis. 2020. 15:349-358. doi.org/10.1080/17460441.2020.1707801
- Early JV, Mullen S, Parish T. A rapid, low pH, nutrient stress, assay to determine the bactericidal activity of compounds against non-replicating Mycobacterium tuberculosis. PLoS One. 2019. 14(10):e0222970. doi: 10.1371/journal.pone.0222970
- Ollinger J, Kumar A, Roberts DM, Bailey MA, Casey A, Parish T. A high-throughput whole cell screen to identify inhibitors of Mycobacterium tuberculosis. PLoSONE 2019. 14(1):e0205479. doi.org/10.1371/journal.pone.0205479
- S. Mandal, S. Njikan, A. Kumar, J.V. Early and T. Parish. The relevance of persisters in tuberculosis drug discovery. Microbiology 2019.165:492-499.
- L. Cleghorn, P. Ray, J. Odingo, A. Kumar, A. Korkegian...T. Parish, P. Wyatt. Identification of morpholinothiophenes as novel Mycobacterium tuberculosis inhibitors targeting QcrB. J Med Chem. 2018. 61: 6592-6608.
- N.S. Chandrasekera, T. Alling, M.A. Bailey, M. Files, J.V. Early...T. Parish. Identification of phenoxyalkylbenzimidazoles with anti-tubercular activity. J. Med Chem. 2015 58:7273-7285.
- Manning AJ, Ovechkina Y, McGillivray A, Flint L, Roberts DM, Parish T. A high content microscopy assay to determine drug activity against intracellular Mycobacterium tuberculosis. Methods. 2017. 127:3-11. doi: 10.1016/j.ymeth.2017.03.022
- J. Ollinger, M. Bailey, A. Casey, S. Florio, T. Alling...T. Parish. A dual read-out assay to evaluate the potency of compounds active against Mycobacterium tuberculosis. PLoS One. 2013. 8: e60531.
- Ioerger TR, O'Malley T, Liao R, Guinn KM, Hickey MJ...Parish T, Sacchettini JC. Identification of new drug targets and resistance mechanisms in Mycobacterium tuberculosis. PLoS One. 2013. 8(9):e75245. doi: 10.1371/journal.pone.0075245