Seattle Children’s Research Institute

Center for Global Infectious Disease Research

Seattle, Washington USA

Member since 2020

Representative

Tanya Parish, PhD, Professor

Team

• Sultan Chowdhury
• Arielle Butts
• Lauren Ames
• Eric Greve

About

Our current research is focused in two main areas: (i) understanding the biology of the global pathogen Mycobacterium tuberculosis; and (ii) discovering and developing novel drugs for tuberculosis (TB) that are effective at curing drug sensitive and drug resistant tuberculosis.

Our current fundamental research addresses mechanisms of antibiotic resistance, the mode of action of antibiotics and the investigation of essential cellular processes in mycobacteria.

Role & Expertise

Our role in the TBDA is to provide microbiological support to evaluate several novel chemical series for their potential as drug candidates for incorporation into a new drug regimen for tuberculosis. We work as a collaborative team to advance the most promising series based on biological and chemical properties. We have attractive chemical series which target cell wall biosynthesis, respiration, pH homeostasis, as well as those active against non-replicating and intracellular bacteria. We run all of the microbiological assays required to underpin compound progression from hit evaluation, lead generation and lead optimization and provide guidance and support for the team in decision-making. In addition, we work on target identification and mode of action for each high priority series using a combination of approaches.

Our applied work encompasses a range of early-stage drug discovery including assay development and high throughput screening, drug target identification and validation, and medicinal and synthetic chemistry.

References

1. Kumar A, Chettiar S, Brown BS, Early J, Ollinger J, Files M, Bailey MA, Korkegian A, Dennison D, McNeil M, Metz J, Osuma A, Curtin M, Kunzer A, Freiberg G, Bruncko M, Kempf D, Parish T Novel chemical entities inhibiting Mycobacterium tuberculosis growth identified by phenotypic high-throughput screening. Scientific reports 2022, 12 (1), 14879. https://doi.org/10.1038/s41598-022-19192-7
2. Gold B, Zhang J, Quezada LL, Roberts J, Ling Y, Wood M, Shinwari W, Goullieux L, Roubert C, Fraisse L, Bacqué E, Lagrange S, Filoche-Rommé B, Vieth M, Hipskind PA, Jungheim LN, Aubé J, Scarry SM, McDonald SL, Li K, Perkowski A, Nguyen Q, Dartois V, Zimmerman M, Olsen DB, Young K, Bonnett S, Joerss D, Parish T, Boshoff HI, Arora K, Barry CE 3rd, Guijarro L, Anca S, Rullas J, Rodríguez-Salguero B, Martínez-Martínez MS, Porras-De Francisco E, Cacho M, Barros-Aguirre D, Smith P, Berthel SJ, Nathan C, Bates RH. Identification of β-Lactams Active against Mycobacterium tuberculosis by a Consortium of Pharmaceutical Companies and Academic Institutions. ACS infectious diseases , 2022, 8 (3 ) 557-573. https://doi.org/10.1021/acsinfecdis.1c00570
3. Ray, P. C.; Huggett, M.; Turner, P. A.; Taylor, M.; Cleghorn, L. A. T.; Early, J.; Kumar, A.; Bonnett, S. A.; Flint, L.; Joerss, D.; Johnson, J.; Korkegian, A.; Mullen, S.; Moure, A. L.; Davis, S. H.; Murugesan, D.; Mathieson, M.; Caldwell, N.; Engelhart, C. A.; Schnappinger, D.; Epemolu, O.; Zuccotto, F.; Riley, J.; Scullion, P.; Stojanovski, L.; Massoudi, L.; Robertson, G. T.; Lenaerts, A. J.; Freiberg, G.; Kempf, D. J.; Masquelin, T.; Hipskind, P. A.; Odingo, J.; Read, K. D.; Green, S. R.; Wyatt, P. G.; Parish, T. Spirocycle MmpL3 Inhibitors with Improved HERG and Cytotoxicity Profiles as Inhibitors of Mycobacterium Tuberculosis Growth. ACS Omega 2021, 6 (3), 2284–2311. https://doi.org/10.1021/acsomega.0c05589.
4. Soares De Melo, C.; Singh, V.; Myrick, A.; Simelane, S. B.; Taylor, D.; Brunschwig, C.; Lawrence, N.; Schnappinger, D.; Engelhart, C. A.; Kumar, A.; Parish, T.; Su, Q.; Myers, T. G.; Boshoff, H. I. M.; Barry, C. E.; Sirgel, F. A.; Van Helden, P. D.; Buchanan, K. I.; Bayliss, T.; Green, S. R.; Ray, P. C.; Wyatt, P. G.; Basarab, G. S.; Eyermann, C. J.; Chibale, K.; Ghorpade, S. R. Antitubercular 2-Pyrazolylpyrimidinones: Structure-Activity Relationship and Mode-of-Action Studies. Journal of Medicinal Chemistry 2021, 64 (1), 719–740. https://doi.org/10.1021/ACS.JMEDCHEM.0C01727.
5. McNeil, M. B.; O’Malley, T.; Dennison, D.; Shelton, C. D.; Sunde, B.; Parish, T. Multiple Mutations in Mycobacterium Tuberculosis MmpL3 Increase Resistance to MmpL3 Inhibitors. mSphere 2020, 5 (5). https://doi.org/10.1128/msphere.00985-20.
6. Early, J.; Ollinger, J.; Darby, C.; Alling, T.; Mullen, S.; Casey, A.; Gold, B.; Ochoada, J.; Wiernicki, T.; Masquelin, T.; Nathan, C.; Hipskind, P. A.; Parish, T. Identification of Compounds with PH-Dependent Bactericidal Activity against Mycobacterium Tuberculosis. ACS Infectious Diseases 2019, 5 (2), 272–280. https://doi.org/10.1021/ACSINFECDIS.8B00256.
7. Melief, E.; Kokoczka, R.; Files, M.; Bailey, M. A.; Alling, T.; Li, H.; Ahn, J.; Misquith, A.; Korkegian, A.; Roberts, D.; Sacchettini, J.; Parish, T. Construction of an Overexpression Library for Mycobacterium Tuberculosis. Biology Methods and Protocols2018, 3 (1). https://doi.org/10.1093/biomethods/bpy009.
8. Cleghorn, L. A. T.; Ray, P. C.; Odingo, J.; Kumar, A.; Wescott, H.; Korkegian, A.; Masquelin, T.; Lopez Moure, A.; Wilson, C.; Davis, S.; Huggett, M.; Turner, P.; Smith, A.; Epemolu, O.; Zuccotto, F.; Riley, J.; Scullion, P.; Shishikura, Y.; Ferguson, L.; Rullas, J.; Guijarro, L.; Read, K. D.; Green, S. R.; Hipskind, P.; Parish, T.; Wyatt, P. G. Identification of Morpholino Thiophenes as Novel Mycobacterium Tuberculosis Inhibitors, Targeting QcrB. Journal of Medicinal Chemistry 2018, 61 (15), 6592–6608. https://doi.org/10.1021/ACS.JMEDCHEM.8B00172.
9. Martinez-Grau, M. A.; Valcarcel, I. C. G.; Early, J. V.; Gessner, R. K.; de Melo, C. S.; de la Nava, E. M. M.; Korkegian, A.; Ovechkina, Y.; Flint, L.; Gravelle, A.; Cramer, J. W.; Desai, P. V.; Street, L. J.; Odingo, J.; Masquelin, T.; Chibale, K.; Parish, T. Synthesis and Biological Evaluation of Aryl-Oxadiazoles as Inhibitors of Mycobacterium Tuberculosis. Bioorganic & Medicinal Chemistry Letters 2018, 28 (10), 1758–1764. https://doi.org/10.1016/j.bmcl.2018.04.028.