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Remembering Professor Amy Christine Anderson
Please cite this article as: Schiffer, Remembering Professor Amy Christine Anderson, Cell Chemical Biology (2016), http://dx.doi.org/10.1016/j.chembiol.2016.09.008
Cell Chemical Biology
Obituary
Remembering Professor Amy Christine Anderson This summer we lost a scientific thought leader, brilliant colleague and researcher, and mentor and friend way before her time. Amy Anderson (1969 – 2016) realized that the Achilles’ heel of many microbial targets, particularly quickly evolving ones with a high propensity of resistance, was the enzyme dihydrofolate reductase (DHFR). Having received a BA in life sciences at MIT (1991) and PhD in biophysics (1997) at Harvard, Amy went on to UCSF to work with Robert M. Stroud, where she launched her career focus on small molecule inhibitors of the folate pathway. Her independent career started at Dartmouth College as an Assistant Professor of Chemistry (2000–2005). In 2005, Amy married her scientific and life partner, Dr. Dennis Wright, whose medicinal chemistry skills complemented her structural biology approaches. In the same year they moved to the University of Connecticut as Associate Professors of Medicinal Chemistry, and their careers and lives flourished. Together they published 39 articles. Their family grew with the arrival of their two sons, Evan and Dean, who provided them with great joy. In 2012, Amy was promoted to Professor and in 2015, she became Head of the Department of Pharmaceutical Science. Motivated by the global need to find antibiotics that avoid resistance, Amy pursued structure-based design to develop anti-pathogenic inhibitors of the folate biosynthetic pathway. Amy leveraged an iterative multidisciplinary approach that was firmly rooted in structural biology. Over her career, she solved over seventy protein structures that informed many follow up studies, such as Amy’s efforts to develop accurate docking methods (Bolstad and Anderson, 2009) and ways to score high potency analogs to avoid hitting unwanted targets (Lamb et al., 2014) and to predict microbial resistance patterns (Reeve et al., 2015a). In addition, her efforts included developing microbiology screening strategy to experimentally evaluate resistance profiles and making new propargyl-linked antifolates. With this multifaceted strategy, Amy and her team of mentees and collabora-
tors successfully targeted both Grampositive and Gram-negative bacteria as well as fungal infections (G-Dayanandan et al., 2014; Liu et al., 2008; Paulsen et al., 2013; Reeve et al., 2015b). Using high-resolution crystal structures of DHFR, including those from both wild-type Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Bacillus anthracis, and Streptococcus pyogenes, Amy and colleagues developed propargyl-linked antifolates effective against trimethoprim resistant Gram-positive bacteria (Estrada et al., 2016). Amy also used the propargyllinked antifolates to increase activity against Gram-negative bacteria such as Enterobacteriaceae. Based on the crystal structure of wild-type DHFR and resistant variants of Klebisiella pneumoniae and Escherichia coli, Amy and Dennis designed, synthesized, and evaluated several compounds that are potent and selective inhibitors of these enzymes (Estrada et al., 2016; Scocchera et al., 2016). These inhibitors were validated with enzyme inhibition, antibacterial activity, cytotoxicity, and in vitro and in vivo pharmacokinetics. These strategies resulted in bacterial DHFR inhibitors that are highly potent, selective, and efficacious (Reeve et al., 2015a; Reeve et al., 2015b; Reeve et al., 2016). In their most recent endeavor, Amy and Dennis branched out to elucidate the antiproliferative effects of the tropolones. They investigated the biological effects of derivatives of a lead-like natural prod-
Amy Christine Anderson
uct, the tropolones. This novel scaffold possesses a metal-chelating group and non-benzenoid aromatic core, presenting interesting opportunities to potentially interact with metalloenzyme drug targets. Amy found that they are potent inhibitors of leukemia cell lines and certain Gramnegative bacteria (Ononye et al., 2014; Ononye et al., 2013). Amy also enjoyed contributing to the scientific community as a leader and mentor, always stepping up and relishing new challenges. She not only served (from 2009) on but became the chair of the NIH study section Drug Discovery and Mechanisms of Antimicrobial Resistance (DDR). Dr. Guangyong Ji, scientific review officer of DDR, wrote ‘‘The scientific community and DDR was lucky to have Amy as Chair from 2013 to 2015. Her dedication and expertise, along with her high quality review efforts, made her an obvious choice for chairing the panel. This position is a high honor that few scientists are able to enjoy, but the honor was truly ours.’’ Amy was also a passionate and dedicated mentor, directing the research of sixteen PhD students and four postdoctoral associates, many of whom graduated with prestigious scholarships. She was awarded the Connecticut Technology Council’s Woman of Innovation in Research award in 2012 and received a UConn Provost’s Special Achievement Award in 2013. In 2015, she was included in the list of 100 Inspiring Women of STEM in Insight into Diversity magazine, and in 2016, she was elected to the Connecticut Academy of Science and Engineering. Throughout her career, whether in her laboratory, department, or on study section she quietly and respectfully guided and led scientists to their best outcome. Always positive, generous, never complaining, she would just step up and get the job done. I came to know Amy Anderson through the Institute for Drug Resistance, where we shared similar perspectives, grounded in experimental structural biology and using a combination of computational and organic chemistry, for approaching and avoiding drug resistance in quickly evolving diseases. From
Cell Chemical Biology 23, September 22, 2016
1041
Please cite this article as: Schiffer, Remembering Professor Amy Christine Anderson, Cell Chemical Biology (2016), http://dx.doi.org/10.1016/j.chembiol.2016.09.008
Cell Chemical Biology
Obituary
there we co-organized, ‘‘Structural Approaches to Overcoming Resistance’’ for the University of Connecticut Northeast Structure Symposium: The Structural Basis of Drug Resistance in 2011. In 2014, Amy also co-chaired the second Gordon Research Conference in Drug Resistance, a conference that I helped found and co-chaired two years prior. Some of the questions Amy posed when the two of us first discussed resistance in 2009 remain at the forefront as issues in drug design: Predicting drug resistance is a major challenge. If one could predict routes of resistance upfront, one might be able to use that information within the first generation of leads rather than ad hoc after field generation. Specifically, Prediction – 1. Resistance often occurs using mutations outside the active site – how can this be better predicted? 2. Can characteristics of drugs or leads be classified as resistancegenerating? For example, it is well-known that flat, aromatic compounds are substrates for efflux pumps. Are there other characteristics, some of which may be underlying – shapes of molecules (long, extended vs compact), pharmacokinetic properties such as AUC or half-life? 3. Are some targets more prone [to resistance] than others? If so, are there strategies that have been successful in resistance-prone targets in one disease state that could be applied to another’’?
After our first workshop Amy wrote: ‘‘The workshop brought together an intellectually diverse group of people whose ideas made me think ‘‘out of the box’’ about drug resistance problems and their solutions.’’ Hopefully Amy’s insights will help to inspire some ‘‘out of the box’’ next-generation antibiotics with a greatly reduced susceptibility to drug resistance. Amy was an amazing person. She was one of the strongest people I’ve known. We lost a generous scientific thought leader, compassionate mentor and role model, and kind friend. Her legacy continues in her sons, husband, family, and friends and the future research of her husband, mentees, and many colleagues. She truly made the world a better place, and she is very sorely missed. ACKNOWLEDGMENTS I would like to acknowledge the support and suggestions of Amy Anderson’s husband and closest collaborator, Dr. Dennis Wright, and her students and colleagues at University of Connecticut, especially Stephanie Reeve, Victoria Robinson, Janet Paulsen, Leslie Lebel, Amy Howe, and Sandra Weller and Guangyong Ji from NIH.
Celia Schiffer1,* 1
Department of Biochemistry and Molecular Pharmacology, Institute of Drug Resistance, University of Massachusetts Medical School, Worcester, MA 01605, USA *Correspondence: celia.schiffer@ umassmed.edu http://dx.doi.org/10.1016/j.chembiol.2016. 09.008 REFERENCES Bolstad, E.S., and Anderson, A.C. (2009). In pursuit of virtual lead optimization: pruning ensembles of receptor structures for increased efficiency and accuracy during docking. Proteins 75, 62–74. Estrada, A., Wright, D.L., and Anderson, A.C. (2016). Antibacterial antifolates: from development through resistance to the next generation. Cold Spring Harb. Perspect. Med. 6, 6.
1042 Cell Chemical Biology 23, September 22, 2016
G-Dayanandan, N., Paulsen, J.L., Viswanathan, K., Keshipeddy, S., Lombardo, M.N., Zhou, W., Lamb, K.M., Sochia, A.E., Alverson, J.B., Priestley, N.D., et al. (2014). Propargyl-linked antifolates are dual inhibitors of Candida albicans and Candida glabrata. J. Med. Chem. 57, 2643–2656. Lamb, K.M., Lombardo, M.N., Alverson, J., Priestley, N.D., Wright, D.L., and Anderson, A.C. (2014). Crystal structures of Klebsiella pneumoniae dihydrofolate reductase bound to propargyl-linked antifolates reveal features for potency and selectivity. Antimicrob. Agents Chemother. 58, 7484– 7491. Liu, J., Bolstad, D.B., Smith, A.E., Priestley, N.D., Wright, D.L., and Anderson, A.C. (2008). Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase. Chem. Biol. 15, 990–996. Ononye, S.N., VanHeyst, M.D., Oblak, E.Z., Zhou, W., Ammar, M., Anderson, A.C., and Wright, D.L. (2013). Tropolones as lead-like natural products: the development of potent and selective histone deacetylase inhibitors. ACS Med. Chem. Lett. 4, 757–761. Ononye, S.N., Vanheyst, M.D., Giardina, C., Wright, D.L., and Anderson, A.C. (2014). Studies on the antiproliferative effects of tropolone derivatives in Jurkat T-lymphocyte cells. Bioorg. Med. Chem. 22, 2188–2193. Paulsen, J.L., Viswanathan, K., Wright, D.L., and Anderson, A.C. (2013). Structural analysis of the active sites of dihydrofolate reductase from two species of Candida uncovers ligand-induced conformational changes shared among species. Bioorg. Med. Chem. Lett. 23, 1279–1284. Reeve, S.M., Gainza, P., Frey, K.M., Georgiev, I., Donald, B.R., and Anderson, A.C. (2015a). Protein design algorithms predict viable resistance to an experimental antifolate. Proc. Natl. Acad. Sci. USA 112, 749–754. Reeve, S.M., Lombardo, M.N., and Anderson, A.C. (2015b). Understanding the structural mechanisms of antibiotic resistance sets the platform for new discovery. Future Microbiol. 10, 1727–1733. Reeve, S.M., Scocchera, E., Ferreira, J.J., G-Dayanandan, N., Keshipeddy, S., Wright, D.L., and Anderson, A.C. (2016). Charged propargyl-linked antifolates reveal mechanisms of antifolate resistance and inhibit trimethoprim-resistant MRSA strains possessing clinically relevant mutations. J. Med. Chem. 59, 6493–6500. Scocchera, E., Reeve, S.M., Keshipeddy, S., Lombardo, M.N., Hajian, B., Sochia, A.E., Alverson, J.B., Priestley, N.D., Anderson, A.C., and Wright, D.L. (2016). Charged nonclassical antifolates with activity against Gram-positive and Gram-negative pathogens. ACS Med. Chem. Lett. 7, 692–696.
Cell Chemical Biology
Obituary
Remembering Professor Amy Christine Anderson This summer we lost a scientific thought leader, brilliant colleague and researcher, and mentor and friend way before her time. Amy Anderson (1969 – 2016) realized that the Achilles’ heel of many microbial targets, particularly quickly evolving ones with a high propensity of resistance, was the enzyme dihydrofolate reductase (DHFR). Having received a BA in life sciences at MIT (1991) and PhD in biophysics (1997) at Harvard, Amy went on to UCSF to work with Robert M. Stroud, where she launched her career focus on small molecule inhibitors of the folate pathway. Her independent career started at Dartmouth College as an Assistant Professor of Chemistry (2000–2005). In 2005, Amy married her scientific and life partner, Dr. Dennis Wright, whose medicinal chemistry skills complemented her structural biology approaches. In the same year they moved to the University of Connecticut as Associate Professors of Medicinal Chemistry, and their careers and lives flourished. Together they published 39 articles. Their family grew with the arrival of their two sons, Evan and Dean, who provided them with great joy. In 2012, Amy was promoted to Professor and in 2015, she became Head of the Department of Pharmaceutical Science. Motivated by the global need to find antibiotics that avoid resistance, Amy pursued structure-based design to develop anti-pathogenic inhibitors of the folate biosynthetic pathway. Amy leveraged an iterative multidisciplinary approach that was firmly rooted in structural biology. Over her career, she solved over seventy protein structures that informed many follow up studies, such as Amy’s efforts to develop accurate docking methods (Bolstad and Anderson, 2009) and ways to score high potency analogs to avoid hitting unwanted targets (Lamb et al., 2014) and to predict microbial resistance patterns (Reeve et al., 2015a). In addition, her efforts included developing microbiology screening strategy to experimentally evaluate resistance profiles and making new propargyl-linked antifolates. With this multifaceted strategy, Amy and her team of mentees and collabora-
tors successfully targeted both Grampositive and Gram-negative bacteria as well as fungal infections (G-Dayanandan et al., 2014; Liu et al., 2008; Paulsen et al., 2013; Reeve et al., 2015b). Using high-resolution crystal structures of DHFR, including those from both wild-type Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Bacillus anthracis, and Streptococcus pyogenes, Amy and colleagues developed propargyl-linked antifolates effective against trimethoprim resistant Gram-positive bacteria (Estrada et al., 2016). Amy also used the propargyllinked antifolates to increase activity against Gram-negative bacteria such as Enterobacteriaceae. Based on the crystal structure of wild-type DHFR and resistant variants of Klebisiella pneumoniae and Escherichia coli, Amy and Dennis designed, synthesized, and evaluated several compounds that are potent and selective inhibitors of these enzymes (Estrada et al., 2016; Scocchera et al., 2016). These inhibitors were validated with enzyme inhibition, antibacterial activity, cytotoxicity, and in vitro and in vivo pharmacokinetics. These strategies resulted in bacterial DHFR inhibitors that are highly potent, selective, and efficacious (Reeve et al., 2015a; Reeve et al., 2015b; Reeve et al., 2016). In their most recent endeavor, Amy and Dennis branched out to elucidate the antiproliferative effects of the tropolones. They investigated the biological effects of derivatives of a lead-like natural prod-
Amy Christine Anderson
uct, the tropolones. This novel scaffold possesses a metal-chelating group and non-benzenoid aromatic core, presenting interesting opportunities to potentially interact with metalloenzyme drug targets. Amy found that they are potent inhibitors of leukemia cell lines and certain Gramnegative bacteria (Ononye et al., 2014; Ononye et al., 2013). Amy also enjoyed contributing to the scientific community as a leader and mentor, always stepping up and relishing new challenges. She not only served (from 2009) on but became the chair of the NIH study section Drug Discovery and Mechanisms of Antimicrobial Resistance (DDR). Dr. Guangyong Ji, scientific review officer of DDR, wrote ‘‘The scientific community and DDR was lucky to have Amy as Chair from 2013 to 2015. Her dedication and expertise, along with her high quality review efforts, made her an obvious choice for chairing the panel. This position is a high honor that few scientists are able to enjoy, but the honor was truly ours.’’ Amy was also a passionate and dedicated mentor, directing the research of sixteen PhD students and four postdoctoral associates, many of whom graduated with prestigious scholarships. She was awarded the Connecticut Technology Council’s Woman of Innovation in Research award in 2012 and received a UConn Provost’s Special Achievement Award in 2013. In 2015, she was included in the list of 100 Inspiring Women of STEM in Insight into Diversity magazine, and in 2016, she was elected to the Connecticut Academy of Science and Engineering. Throughout her career, whether in her laboratory, department, or on study section she quietly and respectfully guided and led scientists to their best outcome. Always positive, generous, never complaining, she would just step up and get the job done. I came to know Amy Anderson through the Institute for Drug Resistance, where we shared similar perspectives, grounded in experimental structural biology and using a combination of computational and organic chemistry, for approaching and avoiding drug resistance in quickly evolving diseases. From
Cell Chemical Biology 23, September 22, 2016
1041
Please cite this article as: Schiffer, Remembering Professor Amy Christine Anderson, Cell Chemical Biology (2016), http://dx.doi.org/10.1016/j.chembiol.2016.09.008
Cell Chemical Biology
Obituary
there we co-organized, ‘‘Structural Approaches to Overcoming Resistance’’ for the University of Connecticut Northeast Structure Symposium: The Structural Basis of Drug Resistance in 2011. In 2014, Amy also co-chaired the second Gordon Research Conference in Drug Resistance, a conference that I helped found and co-chaired two years prior. Some of the questions Amy posed when the two of us first discussed resistance in 2009 remain at the forefront as issues in drug design: Predicting drug resistance is a major challenge. If one could predict routes of resistance upfront, one might be able to use that information within the first generation of leads rather than ad hoc after field generation. Specifically, Prediction – 1. Resistance often occurs using mutations outside the active site – how can this be better predicted? 2. Can characteristics of drugs or leads be classified as resistancegenerating? For example, it is well-known that flat, aromatic compounds are substrates for efflux pumps. Are there other characteristics, some of which may be underlying – shapes of molecules (long, extended vs compact), pharmacokinetic properties such as AUC or half-life? 3. Are some targets more prone [to resistance] than others? If so, are there strategies that have been successful in resistance-prone targets in one disease state that could be applied to another’’?
After our first workshop Amy wrote: ‘‘The workshop brought together an intellectually diverse group of people whose ideas made me think ‘‘out of the box’’ about drug resistance problems and their solutions.’’ Hopefully Amy’s insights will help to inspire some ‘‘out of the box’’ next-generation antibiotics with a greatly reduced susceptibility to drug resistance. Amy was an amazing person. She was one of the strongest people I’ve known. We lost a generous scientific thought leader, compassionate mentor and role model, and kind friend. Her legacy continues in her sons, husband, family, and friends and the future research of her husband, mentees, and many colleagues. She truly made the world a better place, and she is very sorely missed. ACKNOWLEDGMENTS I would like to acknowledge the support and suggestions of Amy Anderson’s husband and closest collaborator, Dr. Dennis Wright, and her students and colleagues at University of Connecticut, especially Stephanie Reeve, Victoria Robinson, Janet Paulsen, Leslie Lebel, Amy Howe, and Sandra Weller and Guangyong Ji from NIH.
Celia Schiffer1,* 1
Department of Biochemistry and Molecular Pharmacology, Institute of Drug Resistance, University of Massachusetts Medical School, Worcester, MA 01605, USA *Correspondence: celia.schiffer@ umassmed.edu http://dx.doi.org/10.1016/j.chembiol.2016. 09.008 REFERENCES Bolstad, E.S., and Anderson, A.C. (2009). In pursuit of virtual lead optimization: pruning ensembles of receptor structures for increased efficiency and accuracy during docking. Proteins 75, 62–74. Estrada, A., Wright, D.L., and Anderson, A.C. (2016). Antibacterial antifolates: from development through resistance to the next generation. Cold Spring Harb. Perspect. Med. 6, 6.
1042 Cell Chemical Biology 23, September 22, 2016
G-Dayanandan, N., Paulsen, J.L., Viswanathan, K., Keshipeddy, S., Lombardo, M.N., Zhou, W., Lamb, K.M., Sochia, A.E., Alverson, J.B., Priestley, N.D., et al. (2014). Propargyl-linked antifolates are dual inhibitors of Candida albicans and Candida glabrata. J. Med. Chem. 57, 2643–2656. Lamb, K.M., Lombardo, M.N., Alverson, J., Priestley, N.D., Wright, D.L., and Anderson, A.C. (2014). Crystal structures of Klebsiella pneumoniae dihydrofolate reductase bound to propargyl-linked antifolates reveal features for potency and selectivity. Antimicrob. Agents Chemother. 58, 7484– 7491. Liu, J., Bolstad, D.B., Smith, A.E., Priestley, N.D., Wright, D.L., and Anderson, A.C. (2008). Structure-guided development of efficacious antifungal agents targeting Candida glabrata dihydrofolate reductase. Chem. Biol. 15, 990–996. Ononye, S.N., VanHeyst, M.D., Oblak, E.Z., Zhou, W., Ammar, M., Anderson, A.C., and Wright, D.L. (2013). Tropolones as lead-like natural products: the development of potent and selective histone deacetylase inhibitors. ACS Med. Chem. Lett. 4, 757–761. Ononye, S.N., Vanheyst, M.D., Giardina, C., Wright, D.L., and Anderson, A.C. (2014). Studies on the antiproliferative effects of tropolone derivatives in Jurkat T-lymphocyte cells. Bioorg. Med. Chem. 22, 2188–2193. Paulsen, J.L., Viswanathan, K., Wright, D.L., and Anderson, A.C. (2013). Structural analysis of the active sites of dihydrofolate reductase from two species of Candida uncovers ligand-induced conformational changes shared among species. Bioorg. Med. Chem. Lett. 23, 1279–1284. Reeve, S.M., Gainza, P., Frey, K.M., Georgiev, I., Donald, B.R., and Anderson, A.C. (2015a). Protein design algorithms predict viable resistance to an experimental antifolate. Proc. Natl. Acad. Sci. USA 112, 749–754. Reeve, S.M., Lombardo, M.N., and Anderson, A.C. (2015b). Understanding the structural mechanisms of antibiotic resistance sets the platform for new discovery. Future Microbiol. 10, 1727–1733. Reeve, S.M., Scocchera, E., Ferreira, J.J., G-Dayanandan, N., Keshipeddy, S., Wright, D.L., and Anderson, A.C. (2016). Charged propargyl-linked antifolates reveal mechanisms of antifolate resistance and inhibit trimethoprim-resistant MRSA strains possessing clinically relevant mutations. J. Med. Chem. 59, 6493–6500. Scocchera, E., Reeve, S.M., Keshipeddy, S., Lombardo, M.N., Hajian, B., Sochia, A.E., Alverson, J.B., Priestley, N.D., Anderson, A.C., and Wright, D.L. (2016). Charged nonclassical antifolates with activity against Gram-positive and Gram-negative pathogens. ACS Med. Chem. Lett. 7, 692–696.