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Karen Joy Shaw

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Karen Joy Shaw is an American microbiologist and discoverer of novel antifungal and antibacterial compounds.  She is best known for her work on aminoglycoside resistance in bacteria[1] as well as leading drug discovery research teams. As Senior Vice President of Biology at Trius Therapeutics, Inc.[2] her work was critical to the development of the oxazolidinone antibiotic tedizolid phosphate (Sivextro) as well as the discovery of the TriBE inhibitors,[3] a novel class of DNA gyrase/Topoisomerase IV antibacterial agents that target both Gram-positive and Gram-negative organisms.[2]  As Chief Scientific Officer at Amplyx Pharmaceuticals,[4] Shaw was responsible for the preclinical development of the novel antifungal fosmanogepix, a first-in-class broad-spectrum antifungal prodrug that is currently in Phase 2 clinical development for the treatment of invasive fungal infections.[5]  She also discovered APX2039, a unique Gwt1 inhibitor[6] that is in preclinical development for the treatment of cryptococcal meningitis.[7]

Early life and education

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Shaw was born in Brooklyn, New York to Shirley and Solon (née Warshawsky) Shaw, and is the second of two daughters. Shaw graduated from Sheepshead Bay High School in Brooklyn, New York in 1972 and received the Elsbeth Kroeber Memorial Award in Biological Science for outstanding scholarship.  She attended Brooklyn College and received her Bachelor of Science in 1976 from Brooklyn College, CUNY, Brooklyn NY and was awarded the Kappa Phi Club Award from the Department of Biology for an outstanding woman senior.  She went on to do graduate work at University of Connecticut, Storrs in the laboratory of C. M. Berg where she received her master's degree in bacterial genetics in 1978 studying transposon mutagenesis and her doctoral degree in 1981 for studies of metabolic pathways in Salmonella typhimurium[8] and Escherichia coli.[9]  She was awarded a Damon Runyon-Walter Winchell postdoctoral fellowship to support her studies on yeast genetics.[10] at Washington University School of Medicine, St. Louis, MO in the laboratory of Maynard V. Olson

Professional career

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Shaw launched her career in drug discovery and development in 1984 at Schering-Plough Research Institute in Kenilworth, NJ, where she spent 15 years with increasing responsibilities in leading teams in discoveries on aminoglycoside resistance mechanisms and diagnostics[11][1] as well as genomic approaches for discovering novel antifungal and antibacterial agents.[12][13] In 1999, Shaw became Team Leader, Infectious Diseases at Johnson & Johnson in San Diego CA where she led the novel use of microarray technologies to investigate mechanisms of action for antibacterial agents as well as the host responses involved in bacterial infections.[14][15] As Senior Vice President of Biology at Trius Therapeutics, Inc.[2] Shaw spearheaded the microbiology efforts at this biotechnology company, including the development of the antibiotic tedizolid phosphate (Sivextro®).  After Trius was acquired by Cubist Pharmaceuticals, Inc., Shaw went on to become Chief Scientific Officer at Amplyx,[4] leading the preclinical development of the first-in-class antifungal fosmanogepix.[5] In addition, she and her team discovered the novel antifungal agent, APX2039, for the treatment of cryptococcal meningitis.[7] As an independent consultant and president of Hearts Consulting Group, LLC, Shaw continues to provides expert advice to Amplyx Pharmaceuticals, Forge Therapeutics and other biotechnology and pharmaceutical companies on antibacterial and antifungal discovery and development.  She also serves as a reviewer/advisor for the non-profit scientific community on CARB-X, GARD-P and at the NIH.[2]

Scientific contributions

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Aminoglycoside resistance/diagnostics. As a leader in the field of aminoglycoside resistance Shaw was involved in the cloning of numerous novel aminoglycoside resistance genes, leading to the development of over 20 DNA diagnostic probes for evaluating aminoglycoside resistance in clinical isolates. These efforts enabled the tracking of world-wide epidemiology of aminoglycoside resistance in clinical isolates and the ability to identify the structure:function relationships among the enzymes responsible for aminoglycoside resistance.[11]

Target Identification for Antibacterial and Antifungal Drug Discovery. At the Schering-Plough Institute, Shaw led the team effort to develop methods for identifying essential genes in E. coli and S. aureus as well as in fungi.[13]  This information was then used to design high throughput screens for identifying leads targeting over 100 targets for antibacterial and antifungal discovery.[12]  At Johnson & Johnson, Shaw's team expanded these efforts using microarray technology to identify  genes that are important in the pathogenesis of bacterial infections in mammalian hosts.[14]

Novel DNA Gyrase inhibitors.  At Trius Pharmaceuticals, Shaw lead the microbiology efforts in designing a screening regimen for novel DNA gyrase/topoisomerase IV program.  These efforts led to the discovery of the TriBE inhibitors, a novel class of agents active against both Gram-positive and Gram-negative bacteria.[16]

Tedizolid discovery and development. As Sr VP of Biology at Trius Therapeutics, Shaw led the microbiology preclinical development efforts, included in the regulatory data packages, for the novel oxazolidinone antibiotic tedizolid phosphate (Sivextro®).[17]  These efforts included elucidating the pre-clinical and clinical microbiology parameters, mechanism of action, and mechanisms of resistance.  Sivextro® was approved for clinical use by the FDA in 2014 .

Antifungal discovery and development.  As Chief Scientific Officer at Amplyx Pharmaceuticals, Shaw led the preclinical development of fosmanogepix, a first-in-class broad spectrum antifungal agent that was in-licensed from Eisai, Co. in 2015.  This molecule is currently in Phase 2 clinical development for the treatment of invasive fungal infections.[5] She also led the discovery of additional novel antifungal agents that target the Gwt1 enzyme in fungal pathogens.  APX2039 was identified, which has properties distinct from fosmanogepix.[18]  It is currently in preclinical development for the treatment of cryptococcal meningitis.

Representative publications

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Shaw has over 100 published articles.

  • Kapoor, M., M. Moloney, Q. A. Soltow, C. M. Pillar and K. J. Shaw. 2019. Evaluation of Resistance Development to the Gwt1 inhibitor Manogepix (APX001A) in Candida Species. Antimicrob Agents Chemother. Oct 14. Antimicrobial Agents & Chemotherapy .01387-19. doi:10.1128/AAC.01387-19[19]
  • Trzoss M., J. A. Covel, M. Kapoor, M. K. Moloney, Q. A. Soltow, P. J. Webb, K. J. Shaw. 2019. Synthesis of analogs of the Gwt1 inhibitor APX001A and in vitro evaluation against Cryptococcus spp. Bioorganic & Medicinal Chemistry Letters doi: https://doi.org/10.1016/j.bmcl. 2019.126713 Epub 2019 Oct 14. doi:10.1016/j.bmcl.2019.126713[20]
  • Shaw KJ, Schell WA, Covel J, Duboc G, Giamberardino C, Kapoor M, Moloney M, Soltow QA, Tenor JL, Toffaletti DL, Trzoss M, Webb P, Perfect JR. 2018. In vitro and in vivo Evaluation of APX001A/APX001 and other Gwt1 inhibitors against Cryptococcus. Antimicrob Agents Chemother. 62(8) e00523-18. DOI: 10.1128/AAC.00523-18[21]
  • Cunningham, M. L., B. P. Kwan, K. J. Nelson, D. C. Bensen, and K. J. Shaw. 2013. Distinguishing on-target versus off-target activity in early antibacterial drug discovery using a macromolecular synthesis assay. J. Biomolecular Screening, 18(9):1018-26.[22]
  • Tari, L., X. Li, M. Trzoss, D. C. Bensen, Z. Chen, T. Lam, J. Zhang, S.- J. Lee, G. Hough, D. Phillipson, S. Akers-Rodriguez, M. L. Cunningham, B. P. Kwan, K. J. Nelson, A. Castellano, J. Locke, V. Brown-Driver, T. M. Murphy, V. S. Ong, C. M. Pillar, D. L. Shinabarger, J. Nix, F. C. Lightstone, S. E. Wong, T. B. Nguyen, K. J. Shaw, J. Finn.  2013. Tricyclic GyrB/ParE (TriBE) Inhibitors: A new class of broad-spectrum dual-targeting antibacterial agents. PLoS One, 8(12):e84409. doi:10.1371/journal.pone.0084409[23]
  • Shaw, K. J. and B. J. Morrow. 2003. Transcriptional profiling and drug discovery.  Current Opinion in Pharmacology 3 :508-512.doi:10.1016/s1471-4892(03)00110-3[24]
  • Hare, R. S., S. S. Walker, T. E. Dorman, J. R. Greene, L.-M. Guzman, T. J. Kenney, M. C. Sulavik, K. Baradaran, C. Houseweart, H. Yu, Z. Foldes, A. Motzer, M. Walbridge, G. H. Shimer Jr., and K. J. Shaw. 2001. Genetic Footprinting in Bacteria. J. Bacteriol. 5:1694-1706. doi:10.1128/JB.183.5.1694-1706.2001[25]
  • Moir, D. T., K. J. Shaw, R. S. Hare, and G. F. Vovis.  1999.  Genomics and Antimicrobial Drug Discovery - A minireview.  Antimicrob. Agents Chemother.  43:439-446. PMID 10049248[13]

References

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  1. ^ a b Shaw, K. J.; Rather, P. N.; Hare, R. S.; Miller, G. H. (1993). "Molecular genetics of aminoglycoside resistance genes and familial relationships of the aminoglycoside-modifying enzymes". Microbiological Reviews. 57 (1): 138–163. doi:10.1128/MR.57.1.138-163.1993. ISSN 0146-0749. PMC 372903. PMID 8385262.
  2. ^ a b c manager, Community. "Karen J. Shaw". REVIVE. Retrieved 2020-12-01.
  3. ^ Tari, Leslie W.; Li, Xiaoming; Trzoss, Michael; Bensen, Daniel C.; Chen, Zhiyong; Lam, Thanh; Zhang, Junhu; Lee, Suk Joong; Hough, Grayson; Phillipson, Doug; Akers-Rodriguez, Suzanne (2013-12-26). "Tricyclic GyrB/ParE (TriBE) Inhibitors: A New Class of Broad-Spectrum Dual-Targeting Antibacterial Agents". PLOS ONE. 8 (12): e84409. Bibcode:2013PLoSO...884409T. doi:10.1371/journal.pone.0084409. ISSN 1932-6203. PMC 3873466. PMID 24386374.
  4. ^ a b "Karen Joy Shaw, Amplyx Pharmaceuticals Inc: Profile and Biography". Bloomberg.com. Retrieved 2020-12-01.
  5. ^ a b c "Fosmanogepix Shows Promise as an Effective Novel Antifungal in POC Trial". Contagion Live. Retrieved 2020-12-01.
  6. ^ Viriyakosol, Suganya; Kapoor, Mili; Okamoto, Sharon; Covel, Jonathan; Soltow, Quinlyn A.; Trzoss, Michael; Shaw, Karen Joy; Fierer, Joshua (2018-11-19). "APX001 and Other Gwt1 Inhibitor Prodrugs Are Effective in Experimental Coccidioides immitis Pneumonia". Antimicrobial Agents and Chemotherapy. 63 (2): e01715–18. doi:10.1128/AAC.01715-18. ISSN 0066-4804. PMC 6355600. PMID 30455238.
  7. ^ a b "Amplyx to Present New Clinical and Preclinical Data for its Two Lead Programs at Upcoming Scientific Conferences | Amplyx". Retrieved 2020-12-01.
  8. ^ Shaw, K J; Berg, C M; Sobol, T J (1980). "Salmonella typhimurium mutants defective in acetohydroxy acid synthases I and II". Journal of Bacteriology. 141 (3): 1258–1263. doi:10.1128/JB.141.3.1258-1263.1980. ISSN 0021-9193. PMC 293821. PMID 6245063.
  9. ^ Shaw, Karen J.; Berg, Claire M. (1979). "ESCHERICHIA COLI K-12 Auxotrophs Induced by Insertion of the Transposable Element Tn5". Genetics. 92 (3): 741–747. doi:10.1093/genetics/92.3.741. ISSN 0016-6731. PMC 1214033. PMID 395018.
  10. ^ Shaw, K J; Olson, M V (1984). "Effects of altered 5'-flanking sequences on the in vivo expression of a Saccharomyces cerevisiae tRNATyr gene". Molecular and Cellular Biology. 4 (4): 657–665. doi:10.1128/MCB.4.4.657. ISSN 0270-7306. PMC 368776. PMID 6371493.
  11. ^ a b Miller, G. H.; Sabatelli, F. J.; Hare, R. S.; Glupczynski, Y.; Mackey, P.; Shlaes, D.; Shimizu, K.; Shaw, K. J.; Aminoglycoside Resistance Study Groups (1997-01-01). "The Most Frequent Aminoglycoside Resistance Mechanisms--Changes with Time and Geographic Area: A Reflection of Aminoglycoside Usage Patterns?". Clinical Infectious Diseases. 24 (Supplement 1): S46–S62. doi:10.1093/clinids/24.Supplement_1.S46. ISSN 1058-4838. PMID 8994779.
  12. ^ a b Hare, Roberta S.; Walker, Scott S.; Dorman, Thomas E.; Greene, Jonathan R.; Guzman, Luz-Maria; Kenney, Teresa J.; Sulavik, Mark C.; Baradaran, Khandan; Houseweart, Chad; Yu, Haiying; Foldes, Zuzana (2001-03-01). "Genetic Footprinting in Bacteria". Journal of Bacteriology. 183 (5): 1694–1706. doi:10.1128/jb.183.5.1694-1706.2001. ISSN 1098-5530. PMC 95055. PMID 11160101.
  13. ^ a b c Moir, Donald T.; Shaw, Karen J.; Hare, Roberta S.; Vovis, Gerald F. (1999-03-01). "Genomics and Antimicrobial Drug Discovery". Antimicrobial Agents and Chemotherapy. 43 (3): 439–446. doi:10.1128/aac.43.3.439. ISSN 1098-6596. PMC 89141. PMID 10049248.
  14. ^ a b Morrow, Brian J.; Shaw, Karen Joy (2002), "DNA Microarray Expression Analysis in Antibacterial Drug Discovery", Pathogen Genomics, New Jersey: Humana Press, pp. 97–112, doi:10.1007/978-1-59259-172-5_8, ISBN 1-59259-172-8
  15. ^ Shaw, K (2003). "Transcriptional profiling and drug discovery". Current Opinion in Pharmacology. 3 (5): 508–512. doi:10.1016/s1471-4892(03)00110-3. ISSN 1471-4892. PMID 14559096.
  16. ^ Tari, Leslie W.; Trzoss, Michael; Bensen, Daniel C.; Li, Xiaoming; Chen, Zhiyong; Lam, Thanh; Zhang, Junhu; Creighton, Christopher J.; Cunningham, Mark L.; Kwan, Bryan; Stidham, Mark (2013). "Pyrrolopyrimidine inhibitors of DNA gyrase B (GyrB) and topoisomerase IV (ParE). Part I: Structure guided discovery and optimization of dual targeting agents with potent, broad-spectrum enzymatic activity". Bioorganic & Medicinal Chemistry Letters. 23 (5): 1529–1536. doi:10.1016/j.bmcl.2012.11.032. PMID 23352267.
  17. ^ Shaw, Karen Joy; Barbachyn, Michael R. (2011). "The oxazolidinones: past, present, and future". Annals of the New York Academy of Sciences. 1241 (1): 48–70. Bibcode:2011NYASA1241...48S. doi:10.1111/j.1749-6632.2011.06330.x. ISSN 0077-8923. PMID 22191526. S2CID 205936937.
  18. ^ Shaw, Karen Joy; Schell, Wiley A.; Covel, Jonathan; Duboc, Gisele; Giamberardino, C.; Kapoor, Mili; Moloney, Molly; Soltow, Quinlyn A.; Tenor, Jennifer L.; Toffaletti, Dena L.; Trzoss, Michael (2018-06-11). "In VitroandIn VivoEvaluation of APX001A/APX001 and Other Gwt1 Inhibitors againstCryptococcus". Antimicrobial Agents and Chemotherapy. 62 (8). doi:10.1128/aac.00523-18. ISSN 0066-4804. PMC 6105804. PMID 29891599.
  19. ^ Kapoor, Mili; Moloney, Molly; Soltow, Quinlyn A.; Pillar, Chris M.; Shaw, Karen Joy (2019-10-14). "Evaluation of Resistance Development to the Gwt1 Inhibitor Manogepix (APX001A) in Candida Species". Antimicrobial Agents and Chemotherapy. 64 (1): e01387–19, /aac/64/1/AAC.01387–19.atom. doi:10.1128/AAC.01387-19. ISSN 0066-4804. PMC 7187586. PMID 31611349.
  20. ^ Trzoss, Michael; Covel, Jonathan A.; Kapoor, Mili; Moloney, Molly K.; Soltow, Quinlyn A.; Webb, Peter J.; Shaw, Karen Joy (2019). "Synthesis of analogs of the Gwt1 inhibitor manogepix (APX001A) and in vitro evaluation against Cryptococcus spp". Bioorganic & Medicinal Chemistry Letters. 29 (23): 126713. doi:10.1016/j.bmcl.2019.126713. PMC 6901109. PMID 31668974.
  21. ^ Shaw, Karen Joy; Schell, Wiley A.; Covel, Jonathan; Duboc, Gisele; Giamberardino, C.; Kapoor, Mili; Moloney, Molly; Soltow, Quinlyn A.; Tenor, Jennifer L.; Toffaletti, Dena L.; Trzoss, Michael (2018-06-11). "In Vitro and In Vivo Evaluation of APX001A/APX001 and Other Gwt1 Inhibitors against Cryptococcus". Antimicrobial Agents and Chemotherapy. 62 (8): e00523–18, /aac/62/8/e00523–18.atom. doi:10.1128/AAC.00523-18. ISSN 0066-4804. PMC 6105804. PMID 29891599.
  22. ^ Cunningham, Mark L.; Kwan, Bryan P.; Nelson, Kirk J.; Bensen, Daniel C.; Shaw, Karen J. (2013-05-17). "Distinguishing On-Target versus Off-Target Activity in Early Antibacterial Drug Discovery Using a Macromolecular Synthesis Assay". Journal of Biomolecular Screening. 18 (9): 1018–1026. doi:10.1177/1087057113487208. ISSN 1087-0571. PMID 23686103. S2CID 22612482.
  23. ^ Tari, Leslie W.; Li, Xiaoming; Trzoss, Michael; Bensen, Daniel C.; Chen, Zhiyong; Lam, Thanh; Zhang, Junhu; Lee, Suk Joong; Hough, Grayson; Phillipson, Doug; Akers-Rodriguez, Suzanne (2013-12-26). Mayer, Claudine (ed.). "Tricyclic GyrB/ParE (TriBE) Inhibitors: A New Class of Broad-Spectrum Dual-Targeting Antibacterial Agents". PLOS ONE. 8 (12): e84409. Bibcode:2013PLoSO...884409T. doi:10.1371/journal.pone.0084409. ISSN 1932-6203. PMC 3873466. PMID 24386374.
  24. ^ Locke, Jeffrey B.; Finn, John; Hilgers, Mark; Morales, Gracia; Rahawi, Shahad; G. C., Kedar; Picazo, Juan José; Im, Weonbin; Shaw, Karen Joy; Stein, Jeffrey L. (2010). "Structure-Activity Relationships of Diverse Oxazolidinones for Linezolid-Resistant Staphylococcus aureus Strains Possessing the cfr Methyltransferase Gene or Ribosomal Mutations". Antimicrobial Agents and Chemotherapy. 54 (12): 5337–5343. doi:10.1128/AAC.00663-10. ISSN 0066-4804. PMC 2981267. PMID 20837751.
  25. ^ Hare, Roberta S.; Walker, Scott S.; Dorman, Thomas E.; Greene, Jonathan R.; Guzman, Luz-Maria; Kenney, Teresa J.; Sulavik, Mark C.; Baradaran, Khandan; Houseweart, Chad; Yu, Haiying; Foldes, Zuzana (2001-03-01). "Genetic Footprinting in Bacteria". Journal of Bacteriology. 183 (5): 1694–1706. doi:10.1128/JB.183.5.1694-1706.2001. ISSN 1098-5530. PMC 95055. PMID 11160101.
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