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]

Contents

Early life and education

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

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

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

Shaw has over 100 published articles.

References

  1. 1 2 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. 1 2 3 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. 1 2 "Karen Joy Shaw, Amplyx Pharmaceuticals Inc: Profile and Biography". Bloomberg.com. Retrieved 2020-12-01.
  5. 1 2 3 "Fosmanogepix Shows Promise as an Effective Novel Antifungal in POC Trial". Contagion Live. 23 October 2020. 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. 1 2 "Amplyx to Present New Clinical and Preclinical Data for its Two Lead Programs at Upcoming Scientific Conferences | Amplyx". Amplyx | Clearing The Path to a Cure. 16 October 2020. Retrieved 2020-12-01.[ permanent dead link ]
  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. 1 2 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. 1 2 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. 1 2 3 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. 1 2 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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